Apparatus and Methods for Loading a Drug Eluting Medical Device

ABSTRACT

Methods and apparatus are disclosed for loading a therapeutic substance or drug within a lumenal space of a hollow wire having a plurality of side openings along a length thereof that forms a hollow drug-eluting stent with a plurality of side drug delivery openings. Loading a drug within the lumenal space of the hollow stent includes a drug filling step, in which the drug is mixed with a solvent or dispersion medium. The lumenal space may be filled with the drug solution or suspension in a reverse fill process and/or a forward fill process. After the drug filling step, a solvent or dispersion medium extracting step is performed to extract the solvent or dispersion medium from within the lumenal space such that only the drug remains within the hollow stent. A stent cleaning step may be performed to an exterior surface of the hollow stent.

CROSS REFERENCE TO RELATED APPLICATION

This application claims benefit under 35 U.S.C. §119(e) to U.S.Provisional Patent Application No. 61/244,050, filed Sep. 20, 2009,which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

Embodiments hereof relate to tubular implantable medical devices thatrelease a therapeutic substance, and apparatuses and methods of fillingsuch medical devices with the therapeutic substance.

BACKGROUND OF THE INVENTION

Drug-eluting implantable medical devices have become popular in recenttimes for their ability to perform their primary function such asstructural support and their ability to medically treat the area inwhich they are implanted. For example, drug-eluting stents have beenused to prevent restenosis in coronary arteries. Drug-eluting stents mayadminister therapeutic agents such as anti-inflammatory compounds thatblock local invasion/activation of monocytes, thus preventing thesecretion of growth factors that may trigger VSMC proliferation andmigration. Other potentially anti-restenotic compounds includeantiproliferative agents, such as chemotherapeutics, which includesirolimus and paclitaxel. Other classes of drugs such asanti-thrombotics, anti-oxidants, platelet aggregation inhibitors andcytostatic agents have also been suggested for anti-restenotic use.

Drug-eluting medical devices may be coated with a polymeric materialwhich, in turn, is impregnated with a drug or a combination of drugs.Once the medical device is implanted at a target location, the drug(s)is released from the polymer for treatment of the local tissues. Thedrug(s) is released by a process of diffusion through the polymer layerfor biostable polymers, and/or as the polymer material degrades forbiodegradable polymers.

Controlling the rate of elution of a drug from the drug impregnatedpolymeric material is generally based on the properties of the polymermaterial. However, at the conclusion of the elution process, theremaining polymer material in some instances has been linked to anadverse reaction with the vessel, possibly causing a small but dangerousclot to form. Further, drug impregnated polymer coatings on exposedsurfaces of medical devices may flake off or otherwise be damaged duringdelivery, thereby preventing the drug from reaching the target site.Still further, drug impregnated polymer coatings are limited in thequantity of the drug to be delivered by the amount of a drug that thepolymer coating can carry and the size of the medical device.Controlling the rate of elution using polymer coatings is alsodifficult.

Accordingly, drug-eluting medical devices that enable increasedquantities of a drug to be delivered by the medical device, and allowfor improved control of the elution rate of the drug, and improvedmethods of forming such medical devices are needed. Co-pending U.S.application Ser. No. 12/500,359, filed Jul. 9, 2009, U.S. ProvisionalApplication No. 61/244,049, filed Sep. 20, 2009, and co-pending U.S.application Ser. No. 12/884,343, each incorporated by reference hereinin their entirety, disclose methods for forming drug-eluting stents withhollow struts. In some applications, such as coronary stents, thediameter of the hollow strut lumen to be filled with the drug ortherapeutic substance is extremely small, e.g. about 0.0015 in., whichmay make filling the lumen difficult. As such apparatus for and methodsof loading a drug within a lumen of a hollow strut of a stent areneeded.

BRIEF SUMMARY OF THE INVENTION

Embodiments hereof are directed to methods and apparatus for loading atherapeutic substance or drug within a lumenal space of a hollow wirehaving a plurality of side openings along a length thereof that forms adrug-eluting hollow stent with a plurality of side drug deliveryopenings. Loading a drug within the lumenal space of the hollow stentincludes a drug filling step in which the drug is mixed with a solventor dispersion medium in order to flow within the lumenal space of thehollow wire. The lumenal space may be filled with the drug solution orsuspension in a reverse fill process through drug delivery openings ofthe hollow stent and/or may be filled with the drug solution orsuspension in a forward fill process through open ends of the hollowstent. After the lumenal space is filled with the drug solution orsuspension, a solvent or dispersion medium extracting step is performedto extract the solvent or dispersion medium from within the lumenalspace such that primarily only the drug or the drug plus one or moreexcipients remain within the hollow stent. A stent cleaning step may beperformed to an exterior surface of the hollow stent.

BRIEF DESCRIPTION OF DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following description of embodiments hereof asillustrated in the accompanying drawings. The accompanying drawings,which are incorporated herein and form a part of the specification,further serve to explain the principles of the invention and to enable aperson skilled in the pertinent art to make and use the invention. Thedrawings are not to scale.

FIG. 1 is a side view of a drug eluting stent formed from a hollow wireaccording to one embodiment hereof.

FIG. 2 is a cross-sectional view taken along line 2-2 of FIG. 1.

FIG. 3 is a sectional view taken along line 3-3 at an end of the hollowwire of FIG. 1.

FIG. 4 is a chart of elution rates for a hollow drug-eluting stent.

FIG. 5 is a flowchart illustrating three main steps of a process forloading a drug or therapeutic substance into a hollow wire of the stentof FIG. 1.

FIG. 5A is a more detailed flowchart of a drug filling step of FIG. 5.

FIG. 5B is a more detailed flowchart of a solvent extraction step ofFIG. 5.

FIG. 5C is a more detailed flowchart of a stent cleaning step of FIG. 5.

FIG. 6 is a chart illustrating the effect of viscosity on drug loading.

FIG. 7A illustrates a hexane based dispersant that has been homogenizedto nano-sized drug particles, while FIG. 7B illustrates a hexane baseddispersant system that has not been homogenized.

FIGS. 8 and 9 are schematic illustrations of an apparatus for forwardfilling a drug eluting stent utilizing high-pressure gas.

FIGS. 10 and 11 are schematic illustrations of an apparatus for forwardfilling a drug eluting stent utilizing disc rotation.

FIGS. 12 and 13 are schematic illustrations of an apparatus for forwardfilling multiple straight hollow wires utilizing a high G centrifugalforce.

FIG. 14 is a schematic illustration of an apparatus for forward fillinga drug eluting stent utilizing a high G centrifugal force.

FIG. 15 is a schematic illustration of an apparatus for forward fillinga drug eluting stent utilizing supercritical CO₂ to precipitate a drugwithin a drug eluting stent.

FIG. 16 is a schematic illustration of an apparatus for forward fillinga drug eluting stent utilizing a syringe.

FIG. 17 is a schematic illustration of an apparatus for forward fillinga drug eluting stent utilizing vibration.

FIG. 18 is a cross-sectional view of a drug eluting stent having abiodegradable liner to assist in forward filling the stent.

FIGS. 19 and 20 are schematic illustrations of a method utilized forforming the biodegradable liner of FIG. 18.

FIG. 21 is a cross-sectional view of a drug eluting stent havingbiodegradable plugs to assist in forward filling the stent.

FIG. 22 is a schematic illustration of an apparatus for reverse fillinga drug eluting stent utilizing a vacuum pump.

FIGS. 23 and 23A are schematic illustrations of apparatuses for reverseor forward filling a drug eluting stent utilizing vacuum pumps and apressure differential.

FIG. 24 is a schematic illustration of an apparatus for reverse fillinga drug eluting stent utilizing vibration.

FIG. 25 is a flowchart of a method for precipitating a drug within thehollow wire of a drug eluting stent, wherein the method utilizes theformation of an azeotrope.

FIGS. 26, 27, and 28 are cross-sectional views illustrating the methodof FIG. 25 to show the formation of the azeotrope within the hollow wireof the drug eluting stent.

FIG. 29 is a flowchart of a method for extracting a solvent from a drugeluting stent, wherein the method utilizes static supercritical CO₂extraction.

FIG. 30 is a flowchart of a method for extracting a solvent from a drugeluting stent, wherein the method utilizes dynamic supercritical CO₂extraction.

FIG. 31 is a schematic illustration of an apparatus for extracting asolvent from a drug eluting stent via cryovac sublimation.

FIG. 32 is a flowchart of a method for extracting a solvent from a drugeluting stent, wherein the method utilizes the cryovac sublimationapparatus of FIG. 31.

FIGS. 33 and 34 are images of cleaning the exterior surface of a stentvia a histobrush.

FIGS. 35, 36, and 37 are flowcharts illustrating various combinations ofmethods described herein for drug filling, solvent extraction, and stentcleaning.

FIGS. 38 and 39 are planar views of a portion of a drug eluting stent,showing one embodiment hereof for eliminating a free end of the stent.

FIG. 40 is a planar view of a portion of a drug eluting stent, showinganother embodiment hereof for eliminating a free end of the stent.

FIG. 41 is a planar view of a portion of a drug eluting stent, showinganother embodiment hereof for eliminating a free end of the stent.

FIG. 42 is a side view of a portion of a drug eluting stent, showing acap to seal an end of the lumen.

FIGS. 43 and 44 are perspective and side sectional views, respectively,of a portion of a drug eluting stent, showing a plug to seal an end ofthe lumen.

FIG. 45 is a side sectional view of a portion of a drug eluting stent,showing a laser cut to seal an end of the lumen.

FIGS. 46-50 illustrate steps of a method for sealing an open end of awire according to another embodiment hereof.

FIGS. 51 and 52 are perspective and side sectional views, respectively,of a portion of a drug eluting stent, showing a cold sleeve to seal anend of the lumen.

DETAILED DESCRIPTION OF THE INVENTION

Specific embodiments of the present invention are now described withreference to the figures, wherein like reference numbers indicateidentical or functionally similar elements. The terms “distal” and“proximal” are used in the following description with respect to aposition or direction relative to the treating clinician. “Distal” or“distally” are a position distant from or in a direction away from theclinician. “Proximal” and “proximally” are a position near or in adirection toward the clinician.

The following detailed description is merely exemplary in nature and isnot intended to limit the invention or the application and uses of theinvention. Drug eluting stents described herein may be utilized in thecontext of treatment of blood vessels such as the coronary, carotid andrenal arteries, or any other body passageways where it is deemed useful.More particularly, drug eluting stents loaded with a therapeuticsubstance by methods described herein are adapted for deployment atvarious treatment sites within the patient, and include vascular stents(e.g., coronary vascular stents and peripheral vascular stents such ascerebral stents), urinary stents (e.g., urethral stents and ureteralstents), biliary stents, tracheal stents, gastrointestinal stents andesophageal stents. Furthermore, there is no intention to be bound by anyexpressed or implied theory presented in the preceding technical field,background, brief summary or the following detailed description.

Hollow Wire Drug-Eluting Stent

An embodiment of a stent 100 to be loaded with a drug in accordance withembodiments hereof is shown in FIGS. 1-3. In particular, stent 100 isformed from a hollow wire 102 and hereinafter may be referred to as ahollow stent or a hollow core stent. Hollow wire 102 defines a lumen orluminal space 103, which may be formed before or after being shaped intoa desired stent pattern. In other words, as used herein, “a stent formedfrom a hollow wire” includes a straight hollow wire shaped into adesired stent pattern, a solid wire having a core that is at leastpartially removed after the solid wire is shaped into a desired stentpattern to have a discontinuous lumen or luminal space therethrough, ora stent constructed from any suitable manufacturing method that resultsin a tubular component formed into a desired stent pattern, the tubularcomponent having a lumen or luminal space extending continuously ordiscontinuously therethrough. As shown in FIG. 1, hollow wire 102 isformed into a series of generally sinusoidal waves including generallystraight segments 106 joined by bent segments or crowns 108 to formgenerally tubular stent 100 that defines a central blood flow passagewayor lumen therethrough. Selected crowns 108 of longitudinally adjacentsinusoids may be joined by, for example, welds 110 as shown in FIG. 1.Methods of loading a drug within a hollow stent in accordance withembodiments hereof are not limited to hollow stents having the patternshown in FIG. 1. Hollow stents formed into any pattern suitable for useas a stent may be loaded with a drug by the methods disclosed herein.For example, and not by way of limitation, hollow stents formed intopatterns disclosed in U.S. Pat. No. 4,800,082 to Gianturco, U.S. Pat.No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 to Wiktor, U.S. Pat.No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 to Boyle, and U.S. Pat.No. 5,019,090 to Pinchuk, each of which is incorporated by referenceherein in its entirety, may be loaded with a drug by the methodsdisclosed herein.

As shown in FIG. 2, hollow wire 102 of stent 100 allows for atherapeutic substance or drug 112 to be deposited within lumen orluminal space 103 of hollow wire 102. Lumen 103 may continuously extendfrom a first end 114 to a second end 114′ of hollow wire 102 or may bediscontinuous such as being only within straight segments 106 and notwithin crowns 108 or may be discontinuous such as being within thestraight segments 106 and a portion of the crowns 108. Although hollowwire 102 is shown as generally having a circular cross-section, hollowwire 102 may be generally elliptical or rectangular in cross-section.Hollow wire 102 may have a wall thickness W_(T) in the range of 0.0004to 0.005 inch with an inner or lumen diameter I_(D) ranging from 0.0005to 0.02 inch. Hollow wire 102 that forms stent 100 may be made from ametallic material for providing artificial radial support to the walltissue, including but not limited to stainless steel, nickel-titanium(nitinol), nickel-cobalt alloy such as MP35N, cobalt-chromium, tantalum,titanium, platinum, gold, silver, palladium, iridium, and the like.Alternatively, hollow wire 102 may be made from a hypotube, which as isknown in the art is a hollow metal tube of very small diameter of thetype typically used in manufacturing hypodermic needles. Alternatively,hollow wire 102 may be formed from a non-metallic material, such as apolymeric material. The polymeric material may be biodegradable orbioresorbable such that stent 100 is absorbed in the body after beingutilized to restore patency to the lumen and/or provide drug delivery.

Hollow wire 102 further includes drug-delivery side openings or ports104 dispersed along its length to permit therapeutic substance or drug112 to be released from lumen 103. Side openings 104 may be disposedonly on generally straight segments 106 of stent 100, only on crowns 108of stent 100, or on both generally straight segments 106 and crowns 108.Side openings 104 may be sized and shaped as desired to control theelution rate of drug 112 from hollow stent 100. More particularly, sideopenings 104 may be slits or may be holes having any suitablecross-section including but not limited to circular, oval, rectangular,or any polygonal cross-section. Larger sized side openings 104 generallypermit a faster elution rate and smaller sized side openings 104generally provide a slower elution rate. Further, the size and/orquantity of side openings 104 may be varied along hollow stent 100 inorder to vary the quantity and/or rate of drug 112 being eluted fromstent 100 at different portions of hollow stent 100. Side openings 104may be, for example and not by way of limitation, 5-30 μm in width ordiameter. Side openings 104 may be provided only on an outwardly facingor ablumenal surface 116 of hollow stent 100, as shown in FIG. 2, onlyon the inwardly facing or lumenal surface 118 of hollow stent 100, onboth surfaces, or may be provided anywhere along the circumference ofwire 102.

In various embodiments hereof, a wide range of therapeutic agents may beutilized as the elutable therapeutic substance or drug 112 contained inlumen 103 of hollow wire 102, with the pharmaceutically effective amountbeing readily determined by one of ordinary skill in the art andultimately depending, for example, upon the condition to be treated, thenature of the therapeutic agent itself, the tissue into which the dosageform is introduced, and so forth. Further, it will be understood by oneof ordinary skill in the art that one or more therapeutic substances ordrugs may be loaded into hollow wire 102. Drug 112 delivered to the areaof a stenotic lesion can be of the type that dissolves plaque materialforming the stenosis or can be an anti-platelet formation drug, ananti-thrombotic drug, or an anti-proliferative drug. Such drugs caninclude TPA, heparin, urokinase, or sirolimus, for example. Of coursestent 100 can be used for delivering any suitable medications to thewalls and interior of a body vessel including one or more of thefollowing: anti-thrombotic agents, anti-proliferative agents,anti-inflammatory agents, anti-migratory agents, agents affectingextracellular matrix production and organization, antineoplastic agents,anti-mitotic agents, anesthetic agents, anti-coagulants, vascular cellgrowth promoters, vascular cell growth inhibitors, cholesterol-loweringagents, vasodilating agents, and agents that interfere with endogenousvasoactive mechanisms.

In accordance with embodiments hereof, hollow stent 100 is loaded orfilled with therapeutic substance or drug 112 prior to implantation intothe body. Open ends 114, 114′ of wire 102 may be closed or sealed eitherbefore or after the drug is loaded within fluid passageway 103 as shownin the sectional view of FIG. 3, which is taken along line 3-3 of FIG.1, and described in more detail herein. Once positioned inside of thebody at the desired location, hollow stent 100 is deployed for permanentor temporary implantation in the body lumen such that therapeuticsubstance 112 may elute from lumen 103 via side openings 104.

FIG. 4 shows a chart of elution rates for a drug-eluting hollow stent.The chart shows the percentage of therapeutic substance eluted as afunction of time. The lines marked 1 and 2 represent a commerciallyavailable drug eluting stent with the therapeutic substance disposed ina polymer on the surface of the stent that has produced desirableclinical efficacy data. The lines marked 3, 4, 5, and 6 are tests usinga hollow stent with the lumen filled with therapeutic substanceaccording to methods described herein, with no polymer on the surface ofthe stent. In particular, the lumen of the hollow stent for the linesmarked 3, 4, 5, and 6 were filled using the azeotrope fill processfollowed by vacuum drying for solvent extraction and stent cleaning viaa histobrush as described in more detail herein. The lines marked 3 and4 are tests using a hollow stent with one 6 μm hole on each strut andlines marked 5 and 6 are tests using a hollow stent with three 10 μmholes on each strut. In particular, the hollow stents used in testsmarked with lines 3 and 5 were filled with a solution of sirolimus andtetrahydrofuran followed by an addition of hexane to precipitate thesirolimus and then the solvent was extracted from the hollow stentlumens and the exterior of the stent cleaned. The hollow stents used intests marked with lines 4 and 6 were filled with a solution ofsirolimus, tetrahydrofuran and an excipient followed by an addition ofhexane to precipitate the sirolimus and then the solvent and thenonsolvent were extracted from the hollow stent lumens and the exteriorof the stent cleaned. The chart of elution rates shows that controlledrelease may be achieved via a hollow stent filled with therapeuticsubstance and a hollow stent filled with therapeutic substance plus anexcipient, and that the hollow filled stent can achieve similar elutioncurves as drug eluting stent with the therapeutic substance disposed ina polymer on the surface of the stent. Hollow filled stent achievingsimilar elution curves as drug-polymer coated stent are expected to havesimilar clinical efficacy while simultaneously being safer without thepolymer coating. In addition, the chart of elution rates show that avariety of elution curves can be achieved from hollow stent filled withtherapeutic substance or a hollow stent filled with therapeuticsubstance plus an excipient.

Overview of Stent Filling Process

A general method of loading a drug within lumen 103 of hollow stent 100in accordance with embodiments hereof is depicted in FIG. 5 to includethe steps of drug filling 520, solvent extracting 538, and stentcleaning 546. More particularly in a drug filling step 520, therapeuticsubstance 112 is generally mixed with a solvent or dispersionmedium/dispersant in order to be loaded into lumen 103 of hollow wire102. In addition, the therapeutic substance 112 can be mixed with anexcipient to assist with elution in addition to the solvent ordispersion medium/dispersant in order to be loaded into lumen 103 ofhollow wire 102. Hereinafter, the term “drug formulation” may be used torefer generally to a therapeutic substance, a solvent or dispersionmedium, and any excipients/additives/modifiers added thereto. Afterlumen 103 of hollow stent 100 is filled with the drug formulation, asolvent/dispersion medium extracting step 538 is performed to extractthe solvent or dispersion medium from within the lumenal space such thatprimarily only therapeutic substance 112 or therapeutic agent 112 andone or more excipients remain within hollow stent 100 to be eluted intothe body. Lastly, a stent cleaning step 546 is performed to hollow stent100 such that the outside surface of hollow stent 100 will besubstantially free of therapeutic agent 112 except where side openings104 are present. Depending on the apparatus and methods used inaccordance herewith, one or more of the steps of drug filling,solvent/dispersion medium extracting and/or stent cleaning may beperformed on hollow wire 102 before or after hollow wire 102 is formedinto stent 100. For example, some of the processes described belowrequire that hollow wire 102 be straight in order to load therapeuticsubstance within the luminal space, while other processes describedbelow may be utilized to fill hollow wire 102 after wire 102 is formedin the desired sinusoidal, helical, or other stent configuration.

Drug Filling Step

FIG. 5A illustrates a more detailed flowchart of drug filling step 520.More particularly in accordance with embodiments hereof, a drugformulation may be loaded into hollow wire 102 via either a forward fillmethod 522 or a reverse fill method 536. Forward fill methods includefilling hollow wire 102 through one or both of open ends 114, 114′thereof while the drug delivery openings 104 are generally blocked orplugged in some manner to prevent leakage therethrough. Reverse fillmethods include filling hollow wire 102 through the plurality of sideopenings 104. In some reverse fill methods, hollow wire 102 is alsofilled via one or both of open ends 114, 114′ thereof in addition tothrough side openings 104. Thus, reverse fill methods leverage the drugdelivery ports 104 as access points to fill the lumenal space of hollowstent 100. By utilizing multiple access points spaced along the lengthof hollow wire 102, the drug formulation may be more evenly introducedinto lumen 103 such that the entire length of lumen 103 may be filledwith the drug formulation. In addition, if a partial blockage of lumen103 or side openings 104 occurs during a reverse fill process, fillingof the remainder of lumen 103 is not seriously affected since thefilling may continue via the remaining side openings 104 as the fillingof the luminal space is not dependent upon filling from end to end.

As mentioned above, in some stent configurations lumen 103 isdiscontinuous along the length of hollow wire 102. For example, asdescribed in copending U.S. patent application Ser. No. 12/884,343,previously incorporated by reference herein, a core of hollow wire 102is left within the crowns of hollow stent 100 to make hollow stent 100more radiopaque. Filling a drug formulation in a forward fill mannerthrough lumen 103 of hollow wire 102 from one and/or the other open ends114, 114′ becomes impossible due to the discontinuous nature of thelumen. Thus, filling in a reverse fill manner is particularlyadvantageous for stents formed from a hollow wire having a discontinuouslumen because the drug formulation laterally fills the separated lumensat the same time through the drug delivery side openings or ports 104.

As shown in FIG. 5A, regardless of whether a forward fill method 522 ora reverse fill method 536 is utilized, therapeutic substance 112 ismixed with a solvent or solvent mixture as a solution 524 or mixed witha dispersion medium as a slurry/suspension 530 before being loaded intohollow wire 102. Solution 524 is a homogeneous mixture in whichtherapeutic substance 112 dissolves within a solvent or a solventmixture. In one embodiment, solution 524 includes a high-capacitysolvent 528 which is an organic solvent that has a high capacity todissolve therapeutic substance 112. High capacity as utilized herein isdefined as an ability to dissolve therapeutic substance 112 atconcentrations greater than 500 mg of substance per milliliter ofsolvent. Examples of high capacity drug dissolving solvents forsirolimus and similar substances include but are not limited totetrahydrofuran (THF), di-chloromethane (DCM), chloroform, anddi-methyl-sulfoxide (DMSO). In addition to the high-capacity solvent,solution 524 may include an excipient 526 in order to assist in drugelution. In one embodiment, excipient 526 may be a surfactant such asbut not limited to sorbitan fatty acid esters such as sorbitanmonooleate and sorbitan monolaurate, polysorbates such as polysorbate20, polysorbate 60, and polysorbate 80, cyclodextrins such as2-hydroxypropyl-beta-cyclodextrin and 2,6-di-O-methyl-beta-cyclodextrin,sodium dodecyl sulfate, octyl glucoside, and low molecular weightpoly(ethylene glycol)s. In another embodiment, excipient 526 may be ahydrophilic agent such as but not limited to salts such as sodiumchloride and other materials such as urea, citric acid, and ascorbicacid. In yet another embodiment, excipient 526 may be a stabilizer suchas but not limited to butylated hydroxytoluene (BHT). Depending on thedesired drug load, a low capacity solvent can also be chosen for itsreduced solubility of therapeutic substance 112. Low capacity is definedas an ability to dissolve therapeutic substance 112 at concentrationstypically below 500 mg of drug per milliliter solvent. Examples of lowcapacity drug dissolving solvents for sirolimus and similar substancesinclude but are not limited to methanol, ethanol, propanol,acetonitrile, ethyl lactate, acetone, and solvent mixtures liketetrahydrafuran/water (9:1 weight ratio). After solution 524 is loadedinto hollow stent 100, therapeutic substance 112 may be precipitated outof the solution, e.g., transformed into solid phase, and the majority ofthe residual solvent and any nonsolvent, if present, may be extractedfrom the lumenal space of hollow wire 102 such that primarily onlytherapeutic substance 112 or therapeutic substance 112 and one or moreexcipients 526 remain to be eluted into the body.

In slurry/suspension form 530, therapeutic substance 112 is notdissolved but rather dispersed as solid particulate in a dispersionmedium, which refers to a continuous medium in liquid form within whichthe solid particles are dispersed. Using a suspension eliminates theneed to precipitate out therapeutic substance 112 from the solvent as isthe case with a solution, because therapeutic substance 112 remains asolid in the dispersion medium when mixed together. Examples ofdispersion mediums with an inability to dissolve therapeutic substance112 depend on the properties of therapeutic substance 112. For example,suitable dispersion mediums with an inability to dissolve sirolimusinclude but are not limited to water, hexane, and other simple alkanes,e.g., C5 thru C10. Certain excipients, suspending agents, surfactants,and/or other additives/modifiers can be added to the drugslurry/suspension to aid in suspension and stabilization, ensure an evendispersion of drug throughout the suspension and/or increase the surfacelubricity of the drug particles. Surfactants thus generally preventtherapeutic substance 112 from floating on the top of or sinking to thebottom of the dispersion medium. Examples of surfactants include but arenot limited to sorbitan fatty acid esters such as sorbitan monooleateand sorbitan monolaurate, polysorbates such as polysorbate 20,polysorbate 60, and polysorbate 80, and cyclodextrins such as2-hydroxypropyl-beta-cyclodextrin and 2,6-di-O-methyl-beta-cyclodextrin.In one embodiment, the targeted amount of therapeutic substance 112 issuspended in the dispersion medium and the appropriate additive/modifieris added on a 0.001 to 10 wt % basis of total formulation. In addition,an excipient such as urea or 2,6-di-Omethyl-beta-cylcodextrin may beadded to slurry/suspension 530 in order to assist in drug elution.

One advantage of utilizing slurry/suspension 530 as opposed to solution524 is that since therapeutic substance 112 is already in solid formwithin the dispersion medium, openings 104 will not become blocked withdried drug solution. More particularly, when filling hollow stent 100with solution 524, a fraction of solution 524 within lumen 103 mayescape or leak through openings 104 onto the outer surface of hollowstent 100. The leaking occurs due to surface tension/capillary action oroutflow from the transferring process. Solution 524 on the outer surfaceof the stent will dry quicker than solution 524 contained within lumen103 of hollow wire 102. The net effect is a cast layer of drug that mayocclude side openings 104, thereby making further solvent extractiondifficult. The residual solvent trapped within the lumenal space canhave a detrimental effect on biocompatibility as well as causecomplications in predicting the effective drug load. By utilizingslurry/suspension 530 rather than solution 524, the drug and dispersionmedium remain separated and a cast layer of drug does not form.

The particle size of therapeutic substance 112 when suspended inslurry/suspension 530 influences various factors, including theviscosity of the suspension and the stability of the suspension meaninghow long the particles remain suspended before settling. In oneembodiment labeled standard slurry/suspension 532, drug particlediameters ranging from 1 micron to 50 microns can be utilized.Therapeutic substance 112 may be pelletized prior to filling the lumenof the hollow wire. The control of particle size distribution orpelletizing of the drug can occur through various paths includingmechanical means such as grinding processes and non-mechanical meanssuch as precipitation processes. When a forward filling method is beingutilized, the pellets are smaller than the lumenal space of the stentsuch that the drug particles can pass through the ends thereof. When areverse filling method is being utilized, the pellets are smaller thanthe openings 104 in the stent such that the drug particles can passtherethrough. The pelletized drug in slurry/suspension 532 may be loadedinto the lumen of the stent by vibration/sonication, pressure filling,or any other suitable technique described herein. Pelletizing thetherapeutic substance provides substantially uniform size of theparticles for improved consistency in dosing and easier loading.

In another embodiment labeled small particle and nanoparticleslurry/suspension 534, drug particle diameters ranging from 1 nanometerto 1000 nanometers can be utilized. Particles in the less than 100nanometer size range are commonly referred to as nanoparticles. Smallparticle size drug and in particular nanoparticles are an attractivecandidate for use in drug delivery as the smaller particles allow formore efficient loading of drug into the stent. More particularly, thedrug particles are significantly smaller than the lumenal space 103 andside openings 104. Thus in a forward fill method, the small particles ofdrug can easily transport into lumen 103 of hollow wire 102 via the openends 114, 114′ of the stent. In a reverse fill method, the drug caneasily traverse side openings 104 to fill lumen 103 of hollow wire 102.

In addition to the aforementioned efficiencies, small particle andnanoparticle drug has advantages in drug delivery. Specifically, as theparticle size is reduced, the solubility of the drug is increased insitu. This benefit becomes more apparent when the particle size isreduced from micron sized particles to nanometer diameter particles.Particles in the nanometer range also have the ability to diffuse aswhole particles from the stent to the tissue by using the concentrationgradient that exists between the drug source and the target tissue. As aresult, the rate of transport from the lumen of stent 100 to the tissueis increased.

Small particle and nanoparticle drug may be created by any suitablemethod, including but not limited to homogenization/microfluidics,precipitation, supercritical CO₂, ball milling, and rod milling. Whencreating a slurry/suspension having nanoparticles, it is important thatthe viscosity of the slurry/suspension is sufficiently low to allowtransport across openings 104 and into the stent. FIG. 6 is a chart thatillustrates how drug loading is affected when particle size is fixedwell below the size of side openings 104 and viscosity is altered. Inthis example, the size of the side openings 104 is 6 um, the particlesize is 300 nm and percent fill weight is defined as the ratio of theamount of drug filled in the stent to the theoretical maximum amount. Inone embodiment, small particle and nanoparticle drug may be generatedvia a multiple-pass homogenization process using a surfactant-stabilizeddispersant, such as hexane or water. For example, a hexane-baseddispersant may be created by mixing hexane with 1% v/v SPAN® 80 and anaqueous-based dispersant may be created by mixing water with 1% v/vTween® 80. Therapeutic substance 112 is added to create aslurry/suspension that is 10% v/v. The mixture may be sonicated for apredetermined time, e.g. 1-60 minutes, to mix the components beforehomogenization. A microfluidics homogenizer or microfluidizer is thenutilized for homogenization, with settings of 28000 psi and 860 passes.FIG. 7A illustrates a hexane based dispersant (5% v/v) that has beenhomogenized to nano-sized drug particles, while FIG. 7B illustrates ahexane based dispersant system (5% v/v) that has not been homogenized.After homogenization, dynamic Light Scattering (DLS) and/or SEM may beused to measure particle distributions to ensure that the particles arehomogenous. The slurry/suspension may then be diluted to the desiredslurry/suspension volume fraction (v/v), and loaded into the lumen ofthe stent by vibration/sonication, pressure filling, or any othersuitable technique described herein.

Drug Filling: Forward Fill High Pressure Gas Embodiment

FIGS. 8 and 9 are schematic illustrations of an apparatus 860 forloading the lumen of a hollow stent in a forward-fill manner with atherapeutic substance in accordance with an embodiment hereof. Apparatus860 is a high-pressure packing bomb utilized to leverage establishedcapillary column packing techniques, with modifications made forslurry/suspension formulation and/or packing technique(s). Moreparticularly, apparatus 860 includes a pressure source 862, a 3-wayvalve 864 including a pressure vent 866, a pressure gauge 868, ahigh-pressure packing unit or bomb 870, and tubing 872 coupling theseitems together. As shown in FIG. 9, packing unit 870 includes a body878, a cap lock 880, a vial or container 882 for holding a suspension ofa therapeutic substance and a dispersion medium, a side port 886 towhich tubing 872 is attached, and a nut 884. Packing unit 870 furtherincludes a cap seal 888, as shown in FIG. 8. Pressurized gas enterspacking unit 870 through tubing 872 to pressurize the therapeuticsubstance suspension held within vial 882. On the exit side of packingunit 870 is a high-pressure fitting 874 for fluidly connecting to afirst end of hollow stent 100 such that the lumenal space of hollow wire102 is in fluid communication with vial 882 to receive the therapeuticsubstance suspension therefrom. An end fitting 876 including a fritdisposed therein is attached to a second end of hollow stent 100 toprevent the therapeutic substance from passing out of hollow stent 100.The frit pore size can range from 0.2 microns to 20 microns depending onthe therapeutic substance slurry/suspension density and the therapeuticsubstance particle size. The aforementioned parts of apparatus 860,except for hollow stent 100, are available from Western FluidsEngineering+MFG, LLC in Wildomar, Calif.

In operation, vial 882 is filled with a slurry/suspension includingtherapeutic substance 112. In one embodiment vial 882 is filled with aslurry/suspension by adding a fixed mass of therapeutic substance 112 tovial 882 followed by a dispersion medium such that the drug per unitvolume concentration ranges from 0.5 mg/ml to 50 mg/ml. The first end ofhollow stent 100 is connected to high-pressure packing unit 870 usinghigh pressure connection 874. In an embodiment, a micro stir bar (notshown) may be added to vial 882, and after vial 882 is placed inside andsealed within packing unit 870, high-pressure packing unit 870 may beplaced on top of a magnetic stir plate. Inert high pressure gas enterspacking unit 870 through side port 886 via tubing 872 and forces theslurry/suspension of therapeutic substance 112 from the vial 882 out ofnut 884, through high pressure fitting 874, and into the lumenal spaceof wire 102 that forms hollow stent 100. The pressurized drugslurry/suspension passes through the lumenal space of hollow stent 100and the solid particles of therapeutic substance 112 are captured by thefrit of end fitting 876. More particularly, the size of the pores of thefrit are selected to allow the dispersion medium to pass or be forcedtherethrough, i.e., downstream thereof, while retaining or capturing thesolid drug or therapeutic substance 112 behind or upstream of the frit,thereby packing/loading the lumenal space of the hollow stent 100 fromthe second end to the first end thereof.

Initial packing pressures can range from 100 to 10,000 psig depending onthe desired packing rate, the drug concentration within theslurry/suspension, and the ratio between the inner diameter of hollowwire 102 and drug particle size. In one example, a 6 inch length ofhollow tubing, with an inside diameter of 0.004″ was filled withsirolimus having a median diameter of approximately 5 um in diameter.The sirolimus was suspended in hexane-isopropanol to achieve a mixtureof 90:10 hexane:isopropanol v/v. A 0.5 um frit was utilized on endfitting 876. Packing bomb 870 was pressurized to 500 psi and held therefor approximately 55 minutes. Thereafter bomb 870 was depressurized toambient and then repressurized to 600 psi. The pressure was thengradually increased from 600 to 900 psi over the next 20 min, and thenfurther increased to 1500 psi in 100 psi increments over 30 minutes. Inexcess of 4 inches of the hollowing tubing was filled with Sirolimus. Inembodiments hereof, a diameter of particles of the therapeutic substancemay be selected from a range of 1 micron to 50 microns. In an embodimentuniform packing of the hollow stent is aided by periodically reducingthe packing pressure to at or near ambient, i.e., depressurizing packingunit 870 to at or near ambient, and subsequently increasing the packingpressure, i.e., re-pressurizing packing unit 870 to the packingpressure, such that periodic pulsatile pressure steps or cycles areemployed. In another embodiment, uniform packing may be aided bygradually ramping-up or increasing the packing pressure as hollow stent100 begins to pack from the second end furthest from packing unit 870toward the first end. In another embodiment, a vacuum may be applied tothe system on the low pressure or downstream side of the frit to assistin drawing the slurry/suspension through the lumenal space of hollowwire 102 toward the frit and to assist in forcing/pulling the dispersionmedium through the frit.

In one embodiment, drug delivery openings 104 of hollow stent 100 aretemporarily blocked or plugged during the forward fill process in orderto minimize leakage of the slurry/suspension as the high pressure gasforces the slurry/suspension through the lumenal space of hollow wire102. In addition, high pressure gas to forward fill a lumenal space of ahollow wire may be utilized to fill a previously formed hollow stent 100as shown in FIG. 8 or may be utilized to fill a straight hollow wire ortube 102 that is subsequently formed into hollow stent 100.

Drug Filling: Forward Fill via Centrifugal Force Embodiments

FIGS. 10 and 11 are schematic illustrations of an apparatus 1090 andmethod for loading the lumen of a hollow stent with a therapeuticsubstance using centrifugal force in accordance with another embodimenthereof. Apparatus 1090 includes a rotatable disc 1092 and a centralfilling tube 1094. Filling tube 1094 is filled with a dry therapeuticsubstance 112. Alternatively, filling tube 1094 is filled with asolution or slurry/suspension containing the therapeutic substance.Central filling tube 1094 is connected to lumen 103 of hollow stent 100.As can be seen, a plurality of hollow stents 100 may be connected tocentral filling tube 1094. Disc 1092 is rotated at a high speed asindicated by the arrows, thereby forcing therapeutic substance fromcentral filling tube 1094 radially outward into lumens 103 of hollowstents 100.

FIGS. 12 and 13 are schematic illustrations of another embodimentutilizing centrifugal force for filling the lumen of multiple hollowstents with a therapeutic substance. A loading apparatus 1291 includestwo upper and lower segments 1297A, 1297B, that mate alonglongitudinally-extending surfaces to form a cylindrical structure.Segments 1297A, 1297B are generally equal halves of the cylindricalloading apparatus 1291 as shown in the side view of FIG. 12. FIG. 13illustrates a top view of segment 1297A. Loading apparatus 1291 may beformed from polycarbonate, stainless steel, and similar materials and isdesigned to hold an array or plurality of straight hollow wires 102 thatare to be filled with therapeutic substance 112. The straight hollowwires 102 may be placed within a loading compartment 1280 having aplurality of grooves 1295 formed on a flat surface of a respectivesegment 1297A, 1297B. Grooves 1295 are precisely machined to be ofsufficient size and shape to securely accommodate the plurality ofstraight hollow wires 102 so that the wires are held firmly in positionduring filling. The bisected design of loading apparatus 1291facilitates loading of the stents to be filled. Apparatus 1291 includesa wedge-shaped reservoir 1293 for containing a drug slurry/suspension tobe loaded within the lumens of the straight hollow wires 102. Loadingcompartment 1280 is positioned downstream of reservoir 1293 and is influid communication with reservoir 1293. Apparatus 1291 further includesa filtering restraining plate 1299 that facilitates the flow of thedispersion medium there-through while permits drug retention upstreamthereof. In one embodiment, the filtering restraining plate is an insertof sintered glass that allows fluid flow therethrough while restrainingthe drug within the lumens of the straight hollow wires 102. A sumpchamber 1296 downstream of filtering restraining plate 1299 captures andcontains the dispersion medium that flows through apparatus 1291 duringthe filling procedure, as will be explained in more detail herein. Whensegments 1297A, 1297B are closed together, rubber gaskets 1298 sealapparatus 1291 such that the slurry/suspension does not leak out of theapparatus during the filling process. Further, a screw cap 1289 having arubber diaphragm (not shown) and a base ring 1287 tightly hold segments1297A, 1297B together.

The filling process begins by placing multiple straight hollow wires 102or tube blanks into grooves 1295 in one half of the loading apparatus1291. Loading apparatus 1291 is then closed by sandwiching straighthollow wires 102 between segments 1297A, 1297B of apparatus 1291, andbase ring 1287 and cap 1289 are screwed into place to seal the unit.Advantageously, to minimize leaking, a compliant rubber coating may beapplied to one or more surfaces of loading compartment 1280 such thatwhen loading apparatus 1291 is closed, the rubber coating seals orprevents leaking through drug delivery openings 104 formed within hollowwires 102. Once sealed, reservoir 1293 is filled with aslurry/suspension including a therapeutic substance by injecting theslurry/suspension through the rubber diaphragm of cap 1289. Apparatus1291 is then placed into a standard centrifuge rotor and a high Gcentrifugal force is applied across the length of hollow wires 102. Thehigh G centrifugal force drives the drug slurry/suspension into thelumens of the hollow wires 102 and packs the volume with drug particlesin a rapid and efficient manner. The speed and time parameters for thecentrifuge rotor depend on various factors, including slurry/suspensioncomposition, slurry/suspension viscosity, drug particle size ordiameter, friction coefficients, and the degree of desired packing. Thecentrifugal force acts along the length of the entire hollow tubes 102and the slurry/suspension moves through hollow wires 102. The dispersionmedium of the slurry/suspension passes or flows through filteringrestraining plate 1299 and is contained within sump chamber 1296, whilethe therapeutic substance of the slurry/suspension remains within thelumens of the hollow wires 102. After filling, the straight hollow wires102 may be formed into the desired stent shape or configuration.

Although described above with respect to a slurry/suspension, apparatus1291 may also be utilized to fill the lumenal space of hollow wires 102with a solution of the therapeutic substance. When utilized with asolution, sump chamber 1296 may be omitted and the restraining plate1299 need not allow passage of liquid therethrough but rather mayfunction to block passage of the solution, thus permitting solutionfilling within the lumenal space of hollow wires 102. After filling, thelumens of straight hollow wires are filled with the drug solution andthe solvent must be subsequently extracted therefrom by any suitablemethod described herein. In general, filling the hollow wires with asolution requires a shorter duration and a lower speed of the centrifugerotor.

With reference to FIG. 14, an embodiment for loading a hollow stent viaa high G centrifugal force is shown. Similar to loading apparatus 1291,loading apparatus 1491 is generally cylindrical and includes upper andlower longitudinal segments that mate along longitudinally-extendingsurfaces to form the generally cylindrical structure (not shown).Apparatus 1491 includes a wedge-shaped reservoir 1493 for containing adrug slurry/suspension, a restraining plate or sintered glass insert1499 that facilitates flow of the dispersion medium therethrough anddrug retention upstream thereof, a sump chamber 1496 to capture andcontain dispersion medium that flows through apparatus 1491 during thefilling procedure, rubber gaskets 1498 to seal apparatus 1491, and a cap1489 and base ring 1487 to close apparatus 1491. However, rather thanhaving grooves to accommodate straight hollow wires, apparatus 1491includes a cylindrical loading compartment 1480 formed therein foraccommodating a single hollow stent 100. Cylindrical loading compartment1480 is a particular diameter and length to accommodate the hollowstent. In one embodiment, a rod or core (not shown) may be insertedthrough the hollow stent during the drug filling process in order tosecure or hold the hollow stent firmly in place. The filling process inwhich a high G centrifugal force is applied across the length of thestent to drive the drug slurry/suspension or solution into the lumenalspace of the stent is the same as described above with respect toapparatus 1291.

Drug Filling: Forward Fill Embodiment Utilizing Supercritical CO₂ forDrug Precipitation

FIG. 15 is a schematic illustration of an apparatus 1585 and method forloading the lumen of a hollow stent with a therapeutic substance inaccordance with another embodiment hereof. Apparatus 1585 includes apressure chamber 1583 (shown in phantom), a supply 1581 forsupercritical carbon dioxide (SCCO₂), a supply line 1579 for introducinga solution of a therapeutic substance in a solvent, such as ethanol, anda recirculation system 1577. Supercritical carbon dioxide is carbondioxide above its critical temperature (31.1° C.) and critical pressure(72.9 atm/7.39 MPa). A hollow stent 100 is disposed in pressure chamber1583. As the solution is pushed through the lumen of hollow stent 100,supercritical carbon dioxide enters the lumen of hollow stent 100through openings 104. The supercritical carbon dioxide interacts withthe solution to precipitate the therapeutic substance such that thetherapeutic substance remains in the lumen of hollow stent 100 and thesolvent, such as ethanol, continues to be recirculated throughrecirculation system 1577. In this embodiment, the properties of SCCO₂are thus utilized as part of the drug filling process in order toprecipitate the therapeutic substance out of the solution. A filter 1573may be located at the exit side of the pressure chamber to capture anyof the therapeutic substance that is pushed through hollow stent 100. Atherapeutic substance supply 1575 is coupled to the recirculation system1577 such that the therapeutic substance and solvent are mixed to beintroduced as a solution into pressure chamber 1583 through supply line1579.

In one embodiment, supercritical carbon dioxide to forward fill a stentmay be utilized to fill a formed hollow stent 100 as shown in FIG. 15 ormay be utilized to fill a straight hollow tube 102 that is subsequentlyformed into hollow stent 100.

Drug Filling: Forward Fill Syringe Embodiment

FIG. 16 is a schematic illustration of an apparatus 1671 and method forloading the lumen of a hollow stent with a therapeutic substance inaccordance with another embodiment hereof. Apparatus 1671 includes asyringe luer connector 1669 and small bore tube coupler 1667 forcoupling the syringe luer connector to hollow stent 100. A syringe (notshown) injects a therapeutic substance into the lumen of hollow stent100 through the syringe luer connector and small bore tube coupler. Thetherapeutic substance may be mixed with a solvent or dispersion mediumto form a solution or slurry/suspension, respectively. Exemplarysolvents or dispersion mediums include ethanol, chloroform, acetone,tetrahydrofuran, dimethyl sulfoxide, ethyl lactate, isopropyl alcohol,acetonitrile, water, and others as would be known to one of ordinaryskill in the art and/or described herein. In one embodiment, drugdelivery openings 104 of hollow stent 100 are blocked or plugged duringthe forward fill process in order to minimize leakage as the syringeinjects the therapeutic substance and solvent/dispersion medium throughthe lumen of the stent. In addition, a syringe to forward fill a stentmay be utilized to fill a hollow stent 100 as shown in FIG. 16 or may beutilized to fill a straight hollow tube 102 that is subsequently formedinto hollow stent 100.

Drug Filling: Forward Fill Embodiment Utilizing Vibration

Forward filling the stent may be assisted by vibration. Vibration may beapplied directly or through a liquid bath. Vibration assists in movingthe therapeutic substance through the lumen of the stent. FIG. 17 showsa schematic representation of an embodiment using vibration to assistdrug loading. Hollow stent 100 is placed in a container 1765 filled witha liquid 1763, such as water. A hopper 1761 including a drug formulationis coupled to one end of the hollow stent 100 and the opposite end ofthe stent is closed. The drug formulation may be a solution or aslurry/suspension that includes the therapeutic substance or a drytherapeutic substance. A pump 1759 is coupled to hopper 1761 to push thedrug formulation through lumen 103 of hollow stent 100. A sonicator 1757or similar vibration producing device is placed in the liquid 1763. Thesonicator 1757 may be held in place by a support structure 1755 andcoupled to a power source 1753. While the drug formulation is beingloading through lumen 103 of hollow stent 100, the sonicator 1757vibrates liquid 1763, thereby vibrating hollow stent 100. The sonicatormay be vibrated at about 20-100 kHz. It would be understood by thoseskilled in the art that vibration techniques may be used with otherloading methods and various means to vibrate the stent may be used. Forexample, the sonicator 1757 or similar vibrating device may contactportions of the stent directly.

Drug delivery openings 104 of hollow stent 100 are blocked or pluggedduring the forward fill process in order to prevent liquid 1763 fromentering hollow stent 100 via openings 104, and to further minimizeleakage as the therapeutic substance and solvent/dispersion medium arepumped into the lumen of the stent. In addition, vibration to forwardfill a stent may be utilized to fill a formed hollow stent 100 as shownin FIG. 17 or may be utilized to fill a straight hollow tube 102 that issubsequently formed into hollow stent 100.

Drug Filling: Forward Fill Embodiments Utilizing Biodegradable Liner orPlugs

In one embodiment, the stent may include a liner to assist in fillingthe stent with the therapeutic substance or drug and to further controlthe rate of drug delivery after stent implantation. More particularly,referring to the cross-sectional view of FIG. 18, stent 1800 may includea bioabsorbable/biodegradable liner 1851 that conforms to an innersurface 1849 of hollow wire 1802. In one embodiment, liner 1851 may havea thickness that ranges between 0.001-0.002 inches. Liner 1851 preventstherapeutic substance 1812 from leaking through side openings 1804during the drug filling step of the manufacturing process. Afterplacement of liner 1851 as described below, stent 1800 may be filled orloaded with therapeutic substance 1812 utilizing any forward fill methoddescribed herein. Regardless of the type of filling method utilized,liner 1851 ensures that therapeutic substance 1812 does not seep out orleak through openings 1804 as lumen 1803 of hollow wire 1802 is filled.

In addition to blocking openings 1804 during manufacture, liner 1851also acts as a mechanism to control release of therapeutic substance1812 into a body vessel after stent 1800 is implanted therein. Liner1851 is formed from a bioabsorbable/biodegradable polymer that dissolvesor breaks down within a vessel such that therapeutic substance 1812 ispermitted to elute into the vessel lumen. In one embodiment, liner 1851is formed out of polylactic acid (PLA), which is a biodegradable plasticthat has been used for many years for medical uses such as biodegradablesutures. Other biodegradable polymers suitable for use in constructingliner 1851 include, for example, polyglycolic acid, collagen,polycaprolactone, hylauric acid, co-polymers of these materials, as wellas composites and combinations thereof. Bioabsorbable polymers suitablefor use in constructing liner 1851 include polymers or copolymers suchas polylactide [poly-L-lactide (PLLA), poly-D-lactide (PDLA)],polyglycolide, polydioxanone, polycaprolactone, polygluconate,polylactic acid-polyethylene oxide copolymers, modified cellulose,collagen, poly(hydroxybutyrate), polyanhydride, polyphosphoester,poly(amino acids), poly(alpha-hydroxy acid) or two or more polymerizablemonomers such as lactide, glycolide, trimethylene carbonate,ε-caprolactone, polyethylene glycol, caprolactone derivatives such as4-tert-butyl caprolactone and N-acetyl caprolactone, poly(ethyleneglycol) bis(carboxymethyl) ether. Each type of biodegradable polymer hasa characteristic degradation rate in the body. Some materials arerelatively fast bioabsorbing materials (weeks to months) while othersare relatively slow bioabsorbing materials (months to years). Thedissolution rate of liner 1851 may be tailored by controlling the typeof bioabsorbable polymer, the thickness and/or density of thebioabsorbable polymer, and/or the nature of the bioabsorbable polymer.In addition, increasing thickness and/or density of a polymeric materialwill generally slow the dissolution rate of the liner. Characteristicssuch as the chemical composition and molecular weight of thebioabsorbable polymer may also be selected in order to control thedissolution rate of the liner.

After stent 1800 is implanted in the vessel, bioabsorbable/biodegradableliner 1851 will breakdown due to exposure to blood flowing through thevessel, thereby allowing therapeutic substance 1812 to be released atthe treatment site and into the bloodstream. In comparison to anexterior bioabsorbable/biodegradable coating used for controllingrelease of therapeutic substance 1812 into a vessel after stent 1800 isimplanted, liner 1851 is more protected during further processing stepssuch as crimping stent 1800 onto a balloon of a balloon catheter (notshown). Further, polymer coatings on exposed surfaces of medical devicesmay flake off or otherwise be damaged during delivery. In comparison,liner 1851 is protected from flaking off or otherwise being damagedduring delivery since liner 1851 is inside hollow wire 102.

FIGS. 19 and 20 illustrate one exemplary method of manufacture for liner1851. More particularly, in one embodiment a hollow tube 1947 of abioabsorbable/biodegradable polymer is fed into lumen 1803 of hollowwire 1802. Hollow wire 1802 may be straight or formed into a stentconfiguration. Similar to balloon forming technology, tube 1947 isclamped at either end, and simultaneously internal pressure and externalheat are applied so that tube 1947 blows out to form liner 1851 thatconfirms to inner surface 1849 of hollow wire 1802. The blowing processthus stretches and thins tube 1947 into liner 1851. Other manufacturingprocesses may be employed to form liner 1851, including but not limitedto gas-assisted injection molding and dipping or pumpingbioabsorbable/biodegradable polymer in liquid form into a hollow stent,with or without masked regions on the exterior surface of the stent.

Referring now to FIG. 21, another embodiment is shown in which the drugdelivery openings 2104 of stent 2100 are filled with plugs 2145 of abioabsorbable/biodegradable polymer. Similar to liner 1851 describedabove, plugs 2145 serve to assist in filling stent 2100 with therapeuticsubstance or drug 2112 and to further control the rate of drug deliveryafter stent implantation. Plugs 2145 substantially fill the drugdelivery side openings and thus extend approximately from the outersurface to the inner surface of hollow wire 2102. Plugs 2145 may have atop surface that is flush with the outside surface of stent 2100 or maybe slightly raised or bumpy. Plugs 2145 prevent therapeutic substance2112 from leaking through the drug delivery side openings during thedrug filling step of the manufacturing process. After placement of plugs2145, stent 2100 may be filled or loaded with therapeutic substance 2112utilizing any forward fill method described herein. In addition toblocking the drug delivery side openings during manufacture, plugs 2145also act as a mechanism to control release of therapeutic substance 2112into a vessel after stent 2100 is implanted because plugs 2145 areformed from a bioabsorbable/biodegradable polymer that dissolves orbreaks down within a vessel such that therapeutic substance 2112 isreleased or emitted into the vessel lumen.

Plugs 2145 may be formed from any bioabsorbable/biodegradable polymerdescribed above with respect to liner 1851. In one embodiment, plugs2145 are formed from the outside surface of hollow wire 2102 and may beformed from any appropriate method, including but not limited tosyringing the bioabsorbable/biodegradable polymer in liquid form intothe drug delivery side openings, manually wedging solid plugs having thesame profile as the drug delivery side openings into the side openings,and dipping the hollow stent into the bioabsorbable/biodegradablepolymer in liquid form into hollow stent, with or without masked regionson the exterior surface of the stent.

Drug Filling: Forward Fill Embodiments Utilizing Drug Formed into SolidRod or Cylinder

In another embodiment, the therapeutic substance is formed into a rod orsolid cylinder with a diameter smaller than the diameter of lumen 103 ofhollow wire 102. The therapeutic substance can be formed into a solidcylinder by combining it with a binder, such as lactose powder, dibasiccalcium phosphate, sucrose, corn starch, microcrystalline cellulose andmodified cellulose, and combinations thereof. The therapeutic substanceand binder are uniformly mixed and pressed into the desired shape, suchas a rod or cylinder shape in this embodiment. The rod is then insertedinto lumen 103 of the hollow wire 102 prior to the hollow wire beingbent into a stent pattern, that is, while the wire is straight. Thehollow wire 102 with the therapeutic substance disposed therein is thenshaped into a stent form, as described above. The therapeutic substancein a solid form provides support to the hollow wire while the hollowwire is being shaped into the stent pattern.

Drug Filling: Reverse and Forward Fill Embodiments Utilizing Pressureand/or Vacuum Pump

FIG. 22 is a schematic illustration of an apparatus 2243 and method forloading the lumen of a hollow stent with a solution or suspension of atherapeutic substance. Apparatus 2243 includes a vacuum pump 2241, amanifold 2239, and a reservoir 2237. Reservoir 2237 is filled with adrug formulation in solution or suspension that includes therapeuticsubstance 112. Vacuum pump 2241 is coupled to manifold 2239 by tubing2235 or other suitable coupling mechanisms. Manifold 2239 is coupled tofirst open ends 114, 114′ of a plurality of hollow stents 100 usingfittings 2233, or other suitable fluid coupling mechanisms, to be influid communication with lumenal spaces 103 of respective hollow wires102 that form hollow stents 100. Hollow stents 100 extend from manifold2239 into the solution or suspension filled reservoir 2237. Inoperation, vacuum pump 2241 draws a vacuum through manifold 2239 andlumenal spaces 103 of hollow stents 100 to draw the drug formulationthrough side openings 104 as well as through opposing open second ends114, 114′ of hollow stents 100. In this manner, the lumenal spaces 103of hollow stents 100 are filled with the drug formulation.

FIG. 23 is a schematic illustration of an apparatus 2331 and method forloading the lumen of a hollow stent with a therapeutic substance inaccordance with another embodiment hereof. Apparatus 2331 includes apressure chamber or vessel 2329 (shown in phantom) and vacuum pumps2327. Pressure chamber 2329 is a pressure-controlled container suitablefor enclosing a hollow stent submerged within a drug suspension. Apressure source 2322 is fluidly connected to the interior of pressurechamber 2329 for controlling the pressure within chamber 2329. Otherpressure chamber configurations are suitable for use herein, includingfor example but not limited to the apparatus of FIG. 23A described belowand the packing bomb described above with respect to FIGS. 8-9.

A hollow stent is disposed in pressure chamber 2329 and a therapeuticsubstance 112 in suspension is provided in or supplied to the pressurechamber. The open ends of the hollow stent extend beyond pressurechamber 2329 and may be sealed to pressure chamber 2329 by compressionfittings (not shown), such as but not limited to a nut and ferulecombination. Vacuum pumps 2327 are coupled to lumen 103 of hollow stent100 via respective opposing open ends 114, 114′. In one embodiment, thepressure inside pressure chamber 2329 is higher than atmosphericpressure and a resulting inward force, represented by arrows 2325,pushes or forces the suspension of therapeutic substance 112 into lumen103 of the hollow stent through side openings 104. Simultaneously,vacuum pumps 2327 cause an outward force, represented by arrows 2323, toaid in drawing the suspension and particularly the solid particles oftherapeutic substance 112 outwardly towards respective open ends 114,114′ and vacuum pumps 2327. In another embodiment, the pressure insidepressure chamber 2329 can be equilibrated with atmospheric pressure andthe pressure differential caused by vacuum pumps 2327 acts to draw thesolid particles of therapeutic substance 112 into the lumenal space ofthe stent and outwardly towards vacuum pumps 2327. Filters 2321 may beprovided at either end of hollow stent 100 such that the therapeuticsubstance “stacks-up” against the filters to tightly pack the lumenalspace 103 of the hollow stent 100 while the dispersion medium is allowedto pass through filters 2321. It would be understood by one of ordinaryskill in the art that the method and apparatus described above may bevaried such that a vacuum is provided along the surface of hollow stent100 through side openings 104 and the therapeutic substance in solutionor suspension may be forced inwardly into the lumenal space from theopen ends 114, 114′ of hollow stent 100. More particularly, the sameset-up or apparatus may be utilized except that the vacuum is applied tothe side openings 104 of hollow stent 100 by developing a vacuum withinpressure chamber 2329. In this embodiment, the vacuum pumps 2327 wouldbe drawing directly from pressure chamber 2329 to develop the vacuum.The open ends 114, 114′ of stent 100 would be immersed in a solution orslurry/suspension of therapeutic substance and thereby be drawn orforced into the lumenal space of stent 100 due to the pressuredifferential. In one embodiment, the solution/suspension may bepressurized such that the vacuum from pressure chamber 2329 and thepressure applied for the solution/suspension force thesolution/suspension to fill the lumenal space of stent 100.

FIG. 23A illustrates another embodiment of a pressure-controlledcontainer suitable for enclosing a hollow stent submerged within a drugsuspension. Apparatus 2331A, which functions similarly to apparatus 2331described above, includes a pressure chamber or vessel 2329A and apressure source 2322A fluidly connected to the interior of pressurechamber 2329A for controlling the pressure within chamber 2329A. In oneembodiment, pressurized gas from pressure source 2322A may assist withmoving the drug suspension. Pressure chamber 2329A includes a removablesealable cap or lid 2324 that allows a hollow stent 100 to be placedinto pressure chamber 2329A chamber. A hollow stent 100 is disposed inpressure chamber 2329A and a therapeutic substance 112 in suspension isprovided in or supplied to the pressure chamber. The open ends of thehollow stent extend beyond pressure chamber 2329A and may be sealed topressure chamber 2329A by compression fittings 2326A, such as but notlimited to nut and ferule combinations. Frit or filters 2321A are placedin line between each end of stent 100 and a vacuum pump 2327A such thatthe therapeutic substance “stacks-up” against the filters to tightlypack the lumenal space 103 of the hollow stent 100 while the dispersionmedium is allowed to pass through filters 2321A. Tube adapters 2328 arealso placed in line between each end of stent 100 and a vacuum pump2327A to allow change in tubing size from the frit/compression fittingto the vacuum pump. As discussed above with respect to FIG. 23, thepressure differential and vacuum pump 2327A pushes or forces thesuspension of therapeutic substance 112 into lumen 103 of the hollowstent through side openings 104.

Pressure chamber and/or vacuum pumps to reverse fill or forward fill astent may be utilized to fill a formed hollow stent 100 as shown inFIGS. 22, 23, and 23A, or may be utilized to fill a straight hollow wireor tube 102 that is subsequently formed into hollow stent 100.

Drug Filling: Reverse Fill Embodiments Utilizing Vibration

In another embodiment, vibration may be used to reverse fill hollowstent 100. Vibration may be applied to hollow stent 100 directly orthrough a liquid bath. Vibration assists in moving a solution orsuspension of the therapeutic substance across drug delivery sideopenings 104 and into lumen 103 of hollow wire 102 that forms stent 100.FIG. 24 shows a schematic representation of an embodiment using anultrasonic bath to assist in drug loading. A container or tube 2419 isfilled with a drug solution or suspension having therapeutic substance112, and hollow stent 100 in its formed configuration is submergedtherein. Tube 2419 is placed within a chamber 2465 of the ultrasonicbath. Chamber 2465 is filled with a liquid 2463, such as water or othersolution. Ultrasonic baths generally include an internal ultrasoundgenerating transducer 2457 built into chamber 2465 to produce ultrasonicwaves in liquid 2463 by changing size in concert with an electricalsignal oscillating at ultrasonic frequency. Alternatively, an externalultrasound generating transducer such as sonication horn 1757 describedabove with respect to FIG. 17 may be placed into liquid 2463 to producevibrations. Internal ultrasound generating transducer 2457 vibratesliquid 2463, thereby vibrating the drug solution or suspension into drugdelivery openings 104 of hollow stent 100. In one embodiment, the drugsolution or suspension is vibrated for a duration of between 1 hour and4 hours. The internal ultrasound generating transducer 2457 may bevibrated at about 20-100 kHz. It would be understood by one of ordinaryskill in the art that vibration techniques may be used with otherloading methods and various means to vibrate the stent may be used. Inone embodiment, ice or another cooling agent may be added to theultrasonic bath as needed to ensure that hollow stent 100 does not warmabove room temperature during the sonication.

After sonication, hollow stent 100 is removed from container 2419 withlumenal space 103 full of the drug solution or suspension, whichincludes therapeutic substance 112, solvent or dispersion medium, and/orany modifiers/additives such as one or more surfactants or excipients,and at least partially dried to remove a majority of the exteriorsolvent or dispersion medium. After drying, the exterior surface ofhollow stent 100 may be coated with the same solution or suspensioncomponents, either as a layer of cast drug solution or a dried drugresidue. Hollow stent 100 may further undergo a solvent extraction stepas described herein and/or a stent cleaning step as described herein toremove any remaining solvent or dispersion medium from the lumenal spaceand/or to remove the cast layer of drug solution or drug residue fromthe outer surface of the stent. Vibration to reverse fill a stent may beutilized to fill a formed hollow stent 100 as shown in FIG. 24, or maybe utilized to fill a straight hollow tube 102 that is subsequentlyformed into hollow stent 100.

Solvent Extraction: Azeotrope to Precipitate Drug

FIGS. 25-28 illustrate an embodiment in which a precipitation method isutilized to separate a drug from a solvent after a solution has beenloaded into the lumenal space of hollow wire. More particularly as shownin a first step 2520 of FIG. 25 and in the cross-sectional view of FIG.26, hollow wire 2602 of stent 2600 is first filled with a solution 2617of therapeutic substance or drug 112 and a first solvent. Therapeuticsubstance 112 is soluble within the first solvent to form solution 2617.The first solvent may be a high or low capacity solvent. In oneembodiment, the first solvent is tetrahydrofuran (THF), although othersolvents suitable for dissolving therapeutic substance 112 may beutilized. THF is a high capacity solvent that dissolves a large amountof various drugs, such as for example sirolimus. As will become apparentby the following description, the first solvent must also be capable offorming an azeotrope with a second or precipitator solvent that is addedlater in the process. Stent 2600 may be filled or loaded with solution2617 utilizing any filling method described herein, however a reversefilling method such as vibration via ultrasonic bath is preferred sothat evaporation of the first solvent may occur quickly through themultiple openings 2604 spaced along the length of stent 2600.

In a second step 2521 of FIG. 25, a second or precipitator solvent isadded to the lumenal space of stent 2600. The second solvent has thefollowing characteristics in order to perform these key functions: (1)the second solvent does not dissolve therapeutic substance 112, i.e.,therapeutic substance 112 is insoluble in the second solvent such thattherapeutic substance 112 precipitates from solution 2617, and (2) thesecond solvent is miscible with the first solvent to ensure properhomogenous mixing and is capable of forming an azeotrope with the firstsolvent. As to the first characteristic of the second precipitatorsolvent listed above, it is noted that the second precipitator solventmay be referred to as a nonsolvent in that it is a substance incapableof dissolving therapeutic substance 112 within solution 2617. As to thesecond characteristic of the second precipitator solvent listed above,an azeotrope is a mixture of two or more liquids in such a ratio thatits composition is not changed when boiled, because the resulting vaporhas the same ratio of constituents as the original mixture. The secondor precipitator solvent is added until the two solvents, i.e., the firstsolvent and the precipitator solvent, reach the azeotrope point. Forexample, when THF is utilized as the first solvent, hexane may beutilized as the second precipitator solvent. Various drugs, includingsirolimus, are insoluble in hexane. Further, THF and hexane are miscibleand form an azeotrope at 46.5% THF and 53.5% hexane by weight (w/w).Since the azeotrope point of a THF/hexane mixture requires 53.5% hexane,a large amount of hexane can be added to solution 2617 in order toensure that therapeutic substance 112 precipitates from solution 2617.In another embodiment, ethanol may be utilized as the first solvent fordissolving the therapeutic substance and water may be utilized as thesecond precipitator solvent that forms an azeotrope with ethanol, aslong as the therapeutic substance is insoluble in water. Afterprecipitation, as shown in the cross-sectional view of FIG. 27,therapeutic substance 112 exists in a solid phase while the twosolvents, i.e., the first solvent and the precipitator solvent, exist asa mixture 2715 in a liquid phase.

The second precipitator solvent may be added to the lumenal space ofstent 2600 in any suitable method. For example, if vibration is beingutilized in a reverse fill method to load hollow stent 100, the secondprecipitator solvent may simply be added to the ultrasound/ultrasonicbath while stent 100 is still submerged in solution 2617 and the secondprecipitator solvent will enter the lumenal space via the drug deliveryside openings of the immersed stent. The second precipitator solventwill cause therapeutic substance 112 to precipitate from the firstsolvent both within the lumenal space of hollow wire 2602 and externalto stent 2600. By precipitating therapeutic substance 112 out ofsolution 2617, the drug and the solvents are separated and a cast layerof dried drug will not form and block openings 2604 upon drying.

Referring now to a third step 2538 of FIG. 25, solvent extraction isperformed to remove the two solvents, i.e., the first solvent and theprecipitator solvent, which exist as liquid mixture 2715 within thelumenal space of hollow wire 2602. Stent 2600, while still immersedwithin mixture 2715 or removed therefrom, is placed in a vacuum oven.Temperature and pressure are controlled such that the azeotrope formedbetween the first solvent and the precipitator solvent becomes volatileand goes into a gaseous phase. For example, ambient pressure may bereduced to approximately 5 torr and temperature may be increased tobetween 30 degrees C. and 40 degrees C. for a THF-hexane to allow rapidevaporation of the solvents. The specific values necessary fortemperature and pressure are dependent upon the specific solvent systemselected however typical values can range between 1×10⁻⁸ torr to 760torr for pressure and 25 degrees C. to 40 degrees C. for temperature.Mixture 2715 will flash off or evaporate from stent 2600, leavingsubstantially only therapeutic substance 112 in solid form within thelumenal space of hollow wire 2602 as shown in the cross-sectional viewof FIG. 28. Very little to no solvents remain within hollow wire 2602.Since the first solvent and the precipitator solvent formed anazeotrope, the solubility of therapeutic substance 112 does not changeas mixture 2715 is evaporated but rather remains in solid form duringthe solvent extraction. Since the composition of an azeotrope does notchange during boiling, therapeutic substance 112 will not dissolve inany remaining mixture 2715 as the azeotrope evaporates. Forming anazeotrope to precipitate a drug within a hollow tubular stent may beutilized within a formed hollow stent or may be utilized to fill astraight hollow tube that is subsequently formed into a hollow stent.

In one embodiment, the first solvent and the precipitator solvent form apositive azeotrope meaning that the combination is more volatile thanthe individual components. A volatile azeotrope results in a relativelylow boiling point for mixture 2715 so that mixture 2715 will flash offor evaporate from stent 2600 quickly and easily. THF and hexanementioned in the previous embodiment may be used as the first solventand the precipitator solvent to form a positive azeotrope having arelatively low boiling point.

In another embodiment, prior to the solvent extraction step 2538described above, water may be added to hollow stent 100 because theaddition of water to a THF/hexane/Sirolimus system can create a hardshell. The hard shell may be utilized for capping stent 2600 so thatdrug is not lost from the inside of the stent during handling thereof.

Solvent/Dispersion Medium Extraction Step of Stent Loading Process

Referring back to FIG. 5, after the stent is filled with a drug, thesecond step of the drug loading process is solvent or dispersion mediumextraction 538. After the lumenal space of the hollow wire 102 is filledwith a drug formulation, any residual solvent/dispersion medium must beextracted from within the lumenal space such that primarily onlytherapeutic substance 112 or therapeutic substance 112 plus one or moreexcipients are located within hollow stent 100 to be eluted into thebody. Thus, the net result of solvent/dispersion medium extraction is adrug, or drug and excipient, filled hollow stent devoid of appreciablelumenal residual solvent/dispersion medium. Solvent/dispersion mediumextraction preferably occurs without affecting or altering thecomposition of therapeutic substance 112. Solvent/dispersion mediumextraction is necessary to make hollow stent 100 a biocompatible implantand is desirable to ensure consistent elution of therapeutic substance112.

FIG. 5B illustrates a more detailed flowchart of the solvent/dispersionmedium extracting step 538 of the loading process, which refers to bothremoval of a solvent from a solution of a therapeutic material heldwithin the luminal space of a hollow stent and removal of a dispersionmedium from a slurry/suspension of a therapeutic material held withinthe luminal space of a hollow stent. More particularly,solvent/dispersion medium extracting step 538 is generally performed viaone or more of a method of supercritical CO₂ extraction 540, a method ofvacuum oven drying 542, and/or a method of cryovac sublimation 544.After solvent/dispersion medium extraction is performed, the lumenalspace of the hollow wire is primarily filled with only drug or drug andexcipient with only negligible quantities of solvent/dispersion medium.Each method is discussed in more detail below.

Solvent/Dispersion Medium Extraction: Vacuum Oven Drying Embodiment

After hollow stent 100 is filled or loaded with a drug formulation,either in solution or suspension, via any filling method describedherein, the stent may be dried within a vacuum oven in order toevaporate any solvent/dispersion medium contained in the lumenal spaceof the hollow wire 102 and precipitate out the therapeutic material.Temperature used for drying is high enough to facilitate solventremoval, while not causing drug degradation during drying. Moreparticularly, the stent may be placed in an oven and dried attemperatures between 25 degrees C. and 40 degrees C. and pressuresbetween 1 torr and 760 torr for up to 24 hours to evaporate the majorityof the exterior solvent/dispersion medium as well as a portion of thesolvent/dispersion medium loaded with the lumenal space. After vacuumoven drying, a dried drug residue or a drug cast often remains on theexterior surface of the stent and residual solvent/dispersion mediumoften remains within the lumenal space.

Solvent/Dispersion Medium Extraction: Supercritical CO₂ Embodiment

With reference to FIGS. 29 and 30, two embodiments utilizingsupercritical carbon dioxide (SCCO₂) extraction to reduce residualsolvents or dispersion mediums within the lumenal space of the hollowstent to negligible quantities are illustrated. These embodiments usethe properties of SCCO₂ to extract residual solvents or dispersionmediums while not removing the previously filled therapeuticsubstance/drug from the lumenal space of the stent. In a first step 2920of a static extraction method of FIG. 29, a stent 100 is filled orloaded with a drug formulation, either in solution or suspension, viaany filling method described herein such that at least the lumenal spaceof hollow wire 102 is filled with the drug formulation. In oneembodiment, the stent may be dried within a vacuum oven prior toundergoing supercritical carbon dioxide (SCCO₂) extraction.

In a second step 2938A of the method of FIG. 29, thesolution/suspension-filled hollow stent 100 is placed inside anextraction vessel. An extraction vessel is a pressure vessel capable ofholding hollow stent 100 and capable of withstanding the temperature andpressures needed for supercritical carbon dioxide. A commonconfiguration for an extraction vessel is a stainless steel cylinderwith each end containing removable caps and fittings to allow flow ofsupercritical carbon dioxide, but other shapes and configurations may beutilized. The extraction vessel is heated to a temperature of between 31degrees C. and 40 degrees C., and then filled with pressurized carbondioxide (CO₂) to a pressure between 1100 psi and 9000 psi until thetemperature and pressure within the extraction vessel are above criticalconditions for CO₂ such that the supercritical carbon dioxide (SCCO₂)behaves as a supercritical fluid by expanding to fill the extractionvessel like a gas but with a density like that of a liquid.Supercritical fluids are by definition at a temperature and pressuregreater than or equal to the critical temperature and pressure of thefluid. Carbon dioxide's critical temperature is 31.1° C. and criticalpressure is 1070.9 psi (72.9 atm), so supercritical carbon dioxide(SCCO₂) describes carbon dioxide at a temperature above 31.1 degrees C.and at a pressure above 1070.9 psi. In a supercritical state, CO₂possesses unique gas-like vapor diffusivities and liquid-like densities.Unlike conventional liquid organic solvents, SCCO₂ has zero surfacetension and thus is capable of penetrating small voids or spaces. SCCO₂also possesses solvent properties similar to organic solvents such thatit is capable of solubilizing the same organic solvents used withsolvents/dispersion mediums that include simple alcohols, alkanes, DCM,THF, and DMSO. In a third step 2938B of the method of FIG. 29,supercritical conditions are maintained within the extraction vessel fora sufficient period of time, such as a holding period or anequilibration time, to allow the SCCO₂ to penetrate the lumenal space ofstent 100 and solubilize the residual solvent/dispersion medium leftoverfrom the filling process. In one embodiment, the equilibration time isbetween 15 minutes and 60 minutes.

In a fourth step 2938C of the method of FIG. 29, after the SCCO₂ haspenetrated the lumenal space of stent 100 and solubilized the residualsolvent/dispersion medium, the extraction vessel is graduallydepressurized to ambient pressure. The pressure reduction is controlledby an expansion valve, which includes an upstream inlet valve attachedto the extraction vessel and a downstream outlet valve attached to theextraction vessel. Opening the expansion valve, which includes openingthe outlet valve while keeping the inlet valve closed, allows flow ofSCCO₂ and residual solvent/dispersion medium out from the extractionchamber and thereby reduces the pressure in the extraction vessel. TheSCCO₂ flow occurs because the outlet of the expansion valve is at alower pressure than the extraction chamber. In one embodiment, theoutlet of the expansion valve is ambient pressure. The resultingpressure reduction or pressure drop across the expansion valve resultsin a volume expansion of the material flowing there-through and hencethe name expansion valve. The outward flow of SCCO2 andsolvent/dispersion medium from the extraction vessel results in theextraction of the solvent/dispersion medium from the lumenal space ofthe stent with the therapeutic material in solid form being left behind.The SCCO₂ reverts to a gas state and evaporates away upondepressurizing. Depending on the specific solvent/dispersion medium inuse as well as the nozzle geometry of the expansion valve, the extractedsolvent/dispersion medium may also change to a gas state and evaporateupon exit of the expansion valve or may be extracted in a liquid state.In an embodiment, additional heating/pressurizing, holding anddepressurizing steps or duty cycles, i.e., steps 2938A-2938C, may berepeatedly or cyclically employed to effect the removal of lumenalresidual solvent/dispersion medium to negligible quantities.

In addition to removing residual solvent/dispersion medium from thelumenal space of the stent, SCCO₂ has also demonstrated a low capacityfor solubilizing certain drugs such as sirolimus. Thus, SCCO₂ is usefulfor removing any drug residue located on the exterior surface of thestent after the filling process. More particularly, during the holdingperiod described above, the SCCO₂ also solubilizes any exterior residualsolvent and a small fraction of the exterior drug residue, resulting ina net cleaning effect on the stent exterior surface.

In a dynamic extraction method illustrated in FIG. 30, method steps3020, 3038A and 3038B are the same as described above with respect tosteps 2920, 2938A and 2938B of the method of FIG. 29. In a first step3020, a stent is filled or loaded with a drug formulation, either insolution or suspension, via any filling method described herein. In asecond step 3038A, the solution/suspension-filled stent is placed insidean extraction vessel, heated to a temperature of between 31 degrees C.and 40 degrees C., and then filled with pressurized carbon dioxide (CO₂)to a pressure between 1100 psi and 9000 psi until the temperature andpressure within the extraction vessel are above critical conditions forCO₂. In a third step 3038B, a holding period is sustained to allow theSCCO₂ to penetrate the lumenal space of the stent and solubilizeresidual solvent/dispersion medium leftover from the filling process. Inone embodiment, the holding period is between 15 minutes and 60 minutes.In a fourth step 3038C of the method of FIG. 30, after the SCCO₂ haspenetrated the lumenal space of hollow stent 100 and solubilized theresidual solvent/dispersion medium, the extraction vessel is allowed toflow dynamically by throttling the expansion valve while maintaining theextraction vessel pressure through a continuous in-flow of a freshsupply of SCCO₂. The continuous in-flow of SCCO2 is achieved bycontinually applying pressurized carbon dioxide to the extraction vesseland throttling the expansion valve to control the exit of material fromthe extraction vessel. In this embodiment, the extraction vessel isnever permitted to depressurize during the extraction process becauseboth the upstream inlet valve and the downstream outlet valve are keptopen. In order to provide the fresh supply of SCCO₂ during dynamicextraction, the CO₂ pump continually adds fresh SCCO₂ to the extractionvessel.

In embodiments hereof, static and/or dynamic SCCO₂ extraction methodsmay be employed in one or more cycles on filled stents for between atotal time of 30 and 120 minutes, at pressures between 2000 and 6000psi. The SCCO₂ extraction methods reduce lumenal solvent levels toinsignificant quantities. Further, in various embodiments, one or morecleaning methods described herein may be employed after the SCCO₂extraction methods in order to clean the exterior of the hollow stent.

Solvent Extraction: Cryovac Sublimation Embodiment

With reference to FIGS. 31 and 32, a method is illustrated in whichcryovac sublimation is utilized to extract the lumenal residual solventsin accordance with embodiments hereof. More particularly, as shown in afirst step 3220 of the method of FIG. 32, a stent is filled or loadedwith a solution including a therapeutic substance via filling methodsdescribed herein that are suitable for solutions such that the lumenalspace of the hollow wire 102 is filled with the drug solution. In oneembodiment, the drug solution includes acetonitrile and sirolimus.

After being filled, a second step 3238A of the method of FIG. 32 is tocool hollow stent 100 in order to precipitate the drug out of thesolution. In particular, referring to FIG. 31, an apparatus 2713suitable for carrying out the cryovac sublimation steps 3238A-3238C ofthe method of FIG. 32 is shown. One or more filled stents are placedinto a sample holder 2711. In one embodiment, additional drug solutionmay be added to sample holder 2711 to keep the filled stents immersedwithin drug solution. Immersing the filled stents in drug solutionprevents the outside surface of the stents from drying which may createa cast layer of dried drug over the drug delivery side openings 104thereby blocking the openings and preventing solvent removal.

Sample holder 2711 is then loaded onto a cooling plate 2701 locatedwithin a processing chamber 2709 of apparatus 2713 and cooled via acoolant that circulates via a coolant supply line 2706 and a coolantreturn line 2708. In one embodiment, in order to minimize evaporation ofsolvent during the loading of sample holder 2711 onto cooling plate2701, apparatus 2713 may include a special pre-conditioning step whereinpressurized inert gas, i.e., pressure above atmospheric pressure, isintroduced into process chamber 2709. Examples of inert gas include butare not limited to argon, helium and nitrogen. The pre-conditioning stepcontinues until the sample holder 2711 is loaded onto cooling plate 2701and process chamber 2709 is closed to the atmosphere. In anotherembodiment, the pre-conditioning step may further continue until sampleholder 2711 is cooled by cooling plate 2701 and the drug precipitatesfrom the drug solution. The temperature and pressure of processingchamber 2709 may be controlled and manipulated such that the temperatureof the drug solution is sufficient for the drug to be precipitated fromthe solvent. More particularly, although temperature is the key factorfor precipitation, pressure control is needed in order to reach thetemperature required for precipitation to occur thus both temperatureand pressure of processing chamber 2709 need be controlled. Thetemperature of cooling plate 2701 may be controlled by the coolanttemperature and how much coolant is supplied through coolant supply line2706 and coolant return line 2708 and the pressure of processing chamber2709 may be controlled via a vacuum pump 2707. In addition, thermocouple2704 may be utilized for monitoring the temperature of cooling plate2701 and pressure sensors 2705 may be utilized for monitoring thepressure within processing chamber 2709. In one embodiment,precipitation of the drug occurs at a temperature of approximately −20degrees C. for cooling plate 2701 and a pressure of 600 torr for processchamber 2709 for a drug solution of acetonitrile and sirolimus. Thecooling rate provided by cooling plate 2701 may be controlled orsufficiently slow to ensure that the precipitated drug can settle orspatially separate from the solvent prior to freezing the solvent suchthat entrainment of drug is minimized during solvent sublimation. Thecontrol of cooling rate is more important as the solution approachesconditions where the drug will precipitate.

After precipitation, the therapeutic substance or drug exists in a solidphase while the solvent is in a liquid phase both within the lumenalspace of the stent and on an exterior of the stent. By precipitating thedrug out of the solvent, the drug and the solvent are separated and acast layer of dried drug will not form to block openings 104 upondrying. As shown in FIG. 32, a third step 3238B of the process includesfurther cooling stent 100 in order to solidify or freeze the solvent.Further cooling of the stent to freeze the solvent thus locks therelative position of the precipitated drug and solvent portions. Inorder to freeze the solvent, sample holder 2711 must reach a temperaturebelow the melting point of the solvent. Depending on the solvent, thetemperature of sample holder 2711 may be required to reach a temperaturebetween −150 degrees C. and 0 degrees C. Examples of solvents includebut are not limited to methanol, ethanol, isopropanol, acetonitrile,acetone, ethyl lactate, tetrahydrofuran, dichloromethane, hexane andwater. The table below lists the melting point temperature for theserepresentative solvents.

Solvent Melting Point (degrees C.) Methanol −97 Isopropanol −89 Ethanol−114 Acetone −95 Acetonitrile −45 Ethyl Lactate −26 Tetrahydrofuran −108Hexane −95 Dichloromethane −97 Water 0

After the solvent has been solidified, a fourth step 3238C of the methodof FIG. 32 is to sublimate the frozen solvent from the stent.Sublimation is a phase transition of a substance from the solid phase tothe gas phase without passing through an intermediate liquid phase. Moreparticularly, a strong vacuum in the order of 1.0 E-3 to 1.0 E-8 Torrmay be applied on processing chamber 2709 via vacuum pump 2707 so thatthe solvent sublimates and leaves behind only solid drug in the lumenalspace of the stent. After solvent removal, the temperature and pressureof processing chamber 2709 is increased to atmospheric conditions andthe stents may be removed from apparatus 2713.

In one example, a hollow stent was sonicated for more than one hour inorder to reverse fill the stent with a solution of sirolimus andacetontrile. After filling the stent with drug solution, the stent wasplaced into sample holder 2711 and additional drug solution was added tocompletely immerse the filled stent. The sample holder was then placedonto cooling plate 2701. Processing chamber 2709 was then evacuated to600 torr and cooling plate 2701 cooled rapidly to approximately −17degrees C. The rate of cooling was then controlled to approximately 3degree C. per minute until precipitation of the drug and solidificationof the solvent was observed. Drug precipitation began about −20 degreesC. and solidification of the solvent was observed about −30 degrees C.Processing chamber 2709 was then evacuated to less than 1×10⁻³ torr andcooling plate 2701 cooled to approximately −45 degrees C. Cooling plate2701 was then allowed to warm at an approximate rate of 0.5 degrees perminute with process chamber 2709 continually evacuated. Sample holder2711 was removed after approximately 45 minutes with the temperature ofcooling plate 2701 at approximately −20 degrees C. As a point ofreference, the temperature of cooling plate 2701 and the temperature ofthe sample may not be the same. The difference in temperature is due tothe design of the cooling plate, location of the thermocouple, locationof the sample holder, and location of the coolant feed and return linesamong other factors. In this example, cooling plate 2701 was constructedof copper and had a large area in comparison to sample holder 2711.Thermocouple 2704 was located near one edge of cooling plate 2701 andcooling holder 2711 was located near the center of cooling plate 2701.Coolant supply line 2706 and coolant return line 2708 were directed tocontact cooling plate 2701 near the center. In this configuration, theindicated temperature of cooling plate 2701 from thermocouple 2704 wouldresult in a warmer temperature than sample holder 2711. Therefore therapid cooling of cooling plate 2701 to approximately −17 degrees C.during the cooling step also means the sample holder and therefore thedrug solution was at a cooler temperature. Similarly, the observedsolidification of the solvent at and indicated temperature of −30degrees C. of cooling plate 2701 means sample holder 2711 and also thesample was at a cooler temperature. Given that the melting point ofacetonitrile is −45 degrees C., the temperature offset between coolingplate 2701 and the samples was approximately 15 degrees C.

In one embodiment, vibratory energy may be applied to apparatus 2713 atany point in the process in order to promote removal of the solvent.During the precipitation and subsequent solvent freezing steps, the drugand solvent may separate into distinct areas where a volume of drug issurrounded by frozen solvent or visa versa. If a volume of frozensolvent is surrounded by drug the trapped solvent may not sublimate. Theaddition of vibratory energy may move the drug such that the drug nolonger completely surrounds the solvent allowing sublimation. Suchvibratory energy may be applied via piezoelectric transducers,oscillating magnets, or any suitable technology compatible withcryogenic temperatures and high vacuum processes.

Stent Cleaning Step of Stent Loading Process

With reference to the method depicted in FIG. 5, after the solvent isextracted from the lumenal space of the stent, a third step of the drugloading method is stent cleaning 546. The above-described methodsemployed to fill a hollow stent with a drug formulation will typicallyresult in all exterior surfaces of the stent, including lumenal,ablumenal, inter-strut and inter-crown surfaces, being coated with thedrug formulation used to fill the stent. Further, even after the solventextraction step, exterior drug residue may still be present on one ormore exterior surfaces of the stent. All exterior surfaces of the stentshould be substantially free of drug in areas where drug delivery sideopenings are not present. Preferably, the stent cleaning process removesthe exterior drug residue without physical manipulation of the stent andwithout disturbing the drug load inside the lumenal space of the stent.

FIG. 5C illustrates a more detailed flowchart of stent cleaning 546 ofthe drug loading process. More particularly, stent cleaning 546 may beperformed by one or more of a solvent-less cleaning method 548, such asa method 550 utilizing a CO₂ dry ice snow sprayer, and/or asolvent-based cleaning method 552, including a solvent-based spraymethod 554, a mechanical manipulation cleaning method 556 utilizing ahistobrush, and/or a solvent-based rinse method 558. Any combination ofthe aforementioned cleaning methods can be employed to clean the stent.The selection of cleaning method(s) may be governed by factors such asthe drug formulation components, the tenaciousness of the driedcomponents on the stent surface, the degree of unwanted drug removalfrom within the stent as a result of cleaning, and the degree ofunwanted solvents being trapped within the stent lumen. Each method isdiscussed in more detail below.

Stent Cleaning Without Solvent

In one embodiment a CO₂ spray cleaning system, also known as a CO₂ dryice snow sprayer, is used for targeted removal of exterior drug residue.A suitable CO₂ spray cleaner is available from Applied SurfaceTechnologies however additional modifications are necessary for use withstents. A CO₂ spray cleaning system takes high purity, liquid CO₂ andexpands it at high velocity across a specially designedorifice-expansion nozzle. Both a temperature and pressure drop occurswith the expansion, thereby converting the liquid CO₂ into solid fineparticulate CO₂ also known as dry ice snow. After expansion, the highvelocity dry ice snow is directed towards the area of the stentcontaining the drug residue. Dry ice contacting the surface of the stentwill cause a decrease in temperature at the stent surface followed bycondensation of water vapor from the surrounding air. Continuedapplication of the dry ice subsequently causes the condensed water tofreeze. The frozen water effectively shields the stent surface fromfurther cleaning by the dry ice. A modification to minimize the frozenwater from forming is the addition of an enclosure to heat the stents.Furthermore In addition, the enclosure may be purged with an inert gassuch as argon or nitrogen to minimize the amount of water vapor present.Cleaning of the stent surface is caused by the momentum transfer of thedry ice snow to the drug residue, akin to bead blasting. After contactwith the stent, the dry ice snow particles are heated by the ambienttemperature and the CO₂ eventually reverts back to the gas state. Thenet effect is a solvent-less cleaning process that removes exterior drugresidue from the stent.

Stent Cleaning With Solvent-Based Spray Systems

A solvent spray system is designed around an ejector system, wherein airor nitrogen serving as the motive fluid entrains a solvent and atomizesthe solvent into fine droplets or mist. The mist is directed at thestent with a high velocity. Depending on the solvent utilized in thespray system, the high velocity mist dissolves or displaces the drugformulation residue from the stent exterior. Various ejector systems maybe utilized. An exemplary ejector system may be a nitrogen pen orairbrush, commonly used for blow-off of dust particles, connected to asmall reservoir of solvent.

The solvent utilized in the solvent spray system is selected to minimizethe amount of drug dissolution, and subsequent removal, from the lumenalspace of the stent. Thus, solvents are chosen based on a limited abilityor inability to solubilize the drug. Examples of solvents with a limitedability to solubilize various therapeutic agents, including sirolimus,include but are not limited to ethanol, isopropyl alcohol, butanol, andcombinations of these alcohols with water at any mass ratio. Theaddition of water serves to suppress the solubilizing potential of thesesimple alcohols for therapeutic agents such as sirolimus that areinsoluble in water. When using low drug solubility solvents, theexterior drug formulation residue is removed primarily by dissolution,followed by displacement due to the spray velocity. Examples of solventswith an inability to solubilize various therapeutic agents, includingsirolimus, include but are not limited to water and simple alkanes (C5to C10). When using non-drug solubilizing solvents, the exterior drugformulation residue is removed primarily by displacement due to thespray velocity.

Stent Cleaning with Mechanical Manipulation via Histobrush

FIG. 33 illustrates another embodiment of stent cleaning in which theexterior surface of the stent is cleaned by mechanical manipulation viaa histobrush 333. The histobrush brush method is manual and involves ahigh degree of stent handling. The user must clean the stent vigorouslyenough to remove all external contaminants while ensuring the mechanicalintegrity is not compromised during the cleaning process. As shown inFIG. 34, a solvent 335 may be added to the brush to assist in cleaninghowever excess solvent can remove drug from the internal portion of thestent and/or add residual solvent, resulting in a large amount ofvariability to the drug loading procedure.

Stent Cleaning with Solvent-Based Rinse Systems

Solvent rinse cleaning systems involve the complete immersion or dippingof hollow stent 100 in a solvent system that has limited or no abilityto dissolve the drug or drug and excipients. Solvent rinse cleaningsystems must tightly control the time the stent is fully immersed.Vortexing, mixing, swirling, or other means of gross fluid agitation mayalso be employed to shear the bulk fluid across the stent surface,thereby cleaning the stent exterior.

The solvent utilized in the solvent rinse system should minimize theamount of drug dissolution, and subsequent removal, from the lumenalspace of hollow stent 100. Thus, solvents are chosen based on a limitedability or inability to solubilize the drug. Examples of solvents with alimited ability to solubilize various therapeutic agents, includingsirolimus, are not limited to ethanol, isopropyl alcohol, butanol, andcombinations of these alcohols with water at any mass ratio. Theaddition of water serves to suppress the solubilizing potential of thesesimple alcohols for therapeutic agents such as sirolimus that areinsoluble in water. When using low drug solubility solvents, theexterior drug formulation residue is removed primarily by dissolution,followed by displacement due to the gross fluid agitation. Examples ofsolvents with an inability to solubilize various therapeutic agents,including sirolimus, include are but not limited to water and simplealkanes (C5 to C10). When using non-drug solubilizing solvents, theexterior drug formulation residue is removed primarily by displacementdue to the gross fluid agitation.

Exemplary Combinations/Processes

In summary, a drug eluting stent such as hollow stent 100 may be loadedwith a drug by a method that includes three main portions or steps asillustrated in FIG. 5, including a drug filling step 520, a solventextracting step 538, and a stent cleaning 546. Various methods for eachof the three main steps of the drug loading process are describedherein, and it will be apparent to one of ordinary skill in the art thata complete loading process in accordance with embodiments hereof mayinclude one or more types of drug filling, one or more types of solventextraction, and one or more types of stent cleaning, and that themethods described herein may be utilized in various combinations.

For example, FIG. 35 illustrates one exemplary combination of apparatusand methods described herein for drug filling, solvent extraction, andstent cleaning. For a drug filling step 3520, the hollow stent 100 isreversed filled utilizing vibration/sonication as described above, fore.g., with reference to the apparatus of FIG. 24. The drug is dissolvedin a high and/or low capacity solvent having one or more excipients. Fora solvent extraction step 3538, supercritical carbon dioxide (SCCO₂)extraction is utilized to reduce the lumenal, residual solvents down tonegligible quantities. A static SCCO₂ extraction method such as thatdescribed with reference to FIG. 29 may be utilized, or a dynamic SCCO₂extraction method such as that described with reference to FIG. 30 maybe utilized. Lastly, the stent is cleaned via a cleaning step 3546 thatutilizes a CO₂ dry ice snow spray system as described above.

FIG. 36 illustrates another exemplary combination of apparatus andmethods described herein for drug filling, solvent extraction, and stentcleaning. For a drug filling step 3620, the stent is reversed filledutilizing vibration/sonication as described above, for e.g., withreference to the apparatus of FIG. 24. The drug is dissolved in a highcapacity solvent having one or more excipients, including at least urea.For a solvent extraction step 3638, cryovac sublimation as describedherein within reference to FIGS. 31 and 32 is utilized to reduce thelumenal, residual solvents down to negligible quantities. Lastly, thestent is cleaned via a cleaning step 3646 that utilizes a CO₂ dry icesnow spray system as described above.

FIG. 37 illustrates another exemplary combination of the apparatus andmethods described herein for drug filling, solvent extraction, and stentcleaning. For a drug filling step 3720, the stent is reversed filledutilizing vibration/sonication as described above, for e.g., withreference to the apparatus of FIG. 24. The drug is suspended in asolvent to form a slurry/suspension, and the size of the drug particlesare preferably in the nanometer range. For a solvent extraction step3738, the stent is dried within a vacuum oven in order to evaporate anysolvent contained in the lumenal space of the hollow wire. Lastly, thestent is cleaned via a cleaning step 3746 that utilizes a CO₂ dry icesnow spray system as described above.

The above described combinations for drug filling, solvent extraction,and stent cleaning are for exemplary purposes only. It will be apparentto one of ordinary skill in the art that various combinations of theabove described methods may be utilized herein for loading a drugeluting stent.

End Sealing Embodiments

When making a drug-eluting hollow stent as described generally hereinand more particularly in co-pending U.S. patent application Ser. No.12/500,359, it may not be desirable for ends 114, 114′ of the stent tobe free ends. Thus, as generally described above, ends 114, 114′ of astent may be welded or otherwise fused to an adjacent crown 108 of thestent, as shown in FIG. 1. However, in some methods of forming andfilling a hollow wire stent, if the therapeutic substance is near thelocation where an end 114, 114′ is fused to a crown, it is possible thatheat will damage the therapeutic substance. Further, if the end 114,114′ remains open during the filling process, the end cannot be weldedto the adjacent crown as shown in FIG. 1 prior to filling the lumen.

FIG. 38 shows an embodiment a method for eliminating a free end of astent. FIG. 38 shows a portion of a hollow stent 1000. End 1014 ofhollow stent 1000 is a free end. Crowns 1008 adjacent end 1014 may bewelded or otherwise fused together as shown at 1010. However, weld 1010is formed prior to filling the lumen 1003 with a therapeutic substance.As shown in FIG. 38, lumen 1003 has been filled with a therapeuticsubstance 1012. Free end 1014 needs to be removed without adverselyaffecting the therapeutic substance. As shown in FIG. 39, a rod 1016 maybe inserted into lumen 1003 from free end 1014. Rod 1016 is pushed adesired distance past crowns 1008 to create a heat buffer zone 1020. Rod1016 may be made of relatively insulative materials, such as a polymeror composite ceramic-polymer material. Examples include polyimide, PTFE,glass reinforced or impregnated PTFE and glass reinforced or impregnatedpolyamide. Alternatively, the rod may be made of a conductive materialwhereby the generated heat is quickly dissipated into the surroundingstent or additional heat sink. Examples of conductive materials includecobalt based alloys, steels, gold, tantalum, platinum-iridium alloys andothers. In either case, the rod may be made radiopaque by addingradiopaque material such as barium sulfate, tungsten or tantalum to thepolymer or polymer composite or the material selected to be radiopaquesuch as tantalum and gold to improve visibility of the implant. Free end1014 may be removed using a laser cutter as indicated at 1022. Due tothe buffer zone created by rod 1016, the therapeutic substance 1012 isnot damaged by the heat from the laser cutter. As necessary the path ofthe laser can be offset to prevent drug damage in adjacent stent membersand/or a heat sink can be added to absorb the excess energy. An exampleof a heat sink would be cooled metal (copper, steel, aluminum, etc.)fashioned as a mandrel on the inside of the stent, sheath contacting theoutside, blocks contacting the outside or sides or other configurationsthat allow contact of the cooled metal with portions of the stentneeding heat protection.

FIG. 40 shows another embodiment for removing a free end 1014 of astent. Free end 1014 (shown dashed) is mechanically removed such as besnipping, cutting, twisting, or other mechanical means known to thoseskilled in the art. Rough end 1024 is smoothed using a long pulse laser,which does not create significant heat, and therefore does not damagethe therapeutic substance 1012.

FIG. 41 shows another embodiment for removing a free end 1014 of astent. A portion of wire 1002 adjacent free end 1014 is flattened. Thiseliminates the therapeutic substance in this area. Free end can beremoved by laser cutting, with the flattened section 1030 serving a heatbuffer zone to prevent damage to the therapeutic substance 1012.

FIGS. 51-52 show another embodiment to remove a free end 1014 of astent. In this embodiment, a cold sleeve 1040 is placed around wire 1002of the stent adjacent end 1014. End 1014 may be laser cut or otherwiseremoved. Cold sleeve 1040 acts as a heat sink and prevents heat fromdamaging the therapeutic substance 1012. Sleeve 1040 may be made from acooled metal or other material that is cooled. Sleeve 1040 may be asleeve with a cold liquid disposed therein.

In some applications, it may be desirable to seal the ends of the lumenof a hollow stent. In one embodiment a cap 1100 may be provided to sealan end of the lumen, as shown in FIG. 42. Cap 1100 may be crimped,fused, melted, glued, or interference fit to the end of the wire. Cap1110 may be made from low melting point metals to fuse to the wire,other metals, polymers, ceramics, or other suitable materials.

In another embodiment shown in FIGS. 43-44, a plug 1150 is inserted intothe lumen to seal the end of the lumen. The wire may be crimped aroundplug 1150, fused glued, or interference fit. Plug may be made from lowmelting point metals to fuse to the wire, other metals, ceramics,polymers, or other suitable materials.

FIGS. 46-50 show a method for sealing an open end 1200 of a wire. Theend is cut or snipped off. However, when cut, the end of the wiredeforms, as shown in FIG. 47, producing a flared end 1202. The edges ofthe flared end may be snipped off, as shown in FIG. 48. The end is thencold worked or otherwise processed to seal the end. However, thisprocess results in a bulbous shaped end 1204, as shown in FIG. 49. Theend may be deburred, as shown in FIG. 50, using a rotating cap 1206.

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofillustration and example only, and not limitation. It will be apparentto persons skilled in the relevant art that various changes in form anddetail can be made therein without departing from the spirit and scopeof the invention. Thus, the breadth and scope of the present inventionshould not be limited by any of the above-described exemplaryembodiments. It will also be understood that each feature of eachembodiment discussed herein, and of each reference cited herein, can beused in combination with the features of any other embodiment.Furthermore, there is no intention to be bound by any expressed orimplied theory presented in the preceding technical field, background,brief summary or the detailed description. All patents and publicationsdiscussed herein are incorporated by reference herein in their entirety.

1. A method of reverse loading a therapeutic substance within a lumenalspace of a hollow wire having a plurality of side openings that forms ahollow stent for drug elution, the method comprising the steps of:preparing a suspension or solution of the therapeutic substance;submerging the hollow stent within the solution or suspension; andapplying a vacuum to a first open end of the hollow stent that isconnected to the lumenal space to draw the solution or suspension intothe lumenal space of the hollow stent via at least the plurality of sideopenings.
 2. The method of claim 1, wherein the step of submergingincludes attaching the first open end of the hollow stent to a manifoldthat is coupled to a vacuum source and positioning the hollow stentwithin a reservoir that holds the solution or suspension such that atleast a portion of the hollow stent that includes the plurality of sideopenings is submerged within the solution or suspension therein.
 3. Themethod of claim 2, wherein a plurality of hollow stents are attached byfirst open ends thereof to the manifold and are positioned within thereservoir such that at least respective portions of the hollow stentsthat include the plurality of side openings are submerged in thesolution or suspension therein.
 4. The method of claim 1, wherein thestep of submerging includes placing the hollow stent within a pressurechamber with the therapeutic substance in suspension and attaching thefirst open end of the hollow stent to a first vacuum source andattaching an opposing second open end of the hollow stent to a secondvacuum source.
 5. The method of claim 4, wherein the step of applying avacuum includes simultaneously operating the first and second vacuumsources to pull a vacuum that draws the therapeutic substance insuspension into the lumenal space of the hollow stent via the pluralityof side openings.
 6. The method of claim 5, further comprising:pressurizing the pressure chamber to greater than ambient pressure toforce the therapeutic substance in suspension into the lumenal space ofthe hollow stent via the plurality of side openings, such that the stepof applying a vacuum aids in drawing the therapeutic substance insuspension into the lumenal space via the plurality of side openings andoutward through the lumenal space towards respective first and secondopen ends of the hollow stent.
 7. The method of claim 6, furthercomprising: using a filtering means at each of the first and second openends of the hollow stent to prevent solid particles of the therapeuticsubstance from passing therethrough while permitting a dispersion mediumof the suspension to pass such that the therapeutic substance packswithin the lumenal space of the hollow stent.
 8. The method of claim 1,wherein the therapeutic substance is in suspension and a dispersionmedium of the suspension is selected from the group consisting of waterand C5-C10 alkanes and the suspension also includes surfactants tostabilize dispersion of the therapeutic substance within the suspension.9. The method of claim 8, wherein the dispersion medium is water, thesurfactant is a polysorbate, and the therapeutic substance is sirolimus.10. The method of claim 8, wherein the dispersion medium is hexane, thesurfactant is a sorbitan fatty acid ester, and the therapeutic substanceis sirolimus.
 11. The method of claim 1, wherein the therapeuticsubstance is in solution and a solvent of the solution is ahigh-capacity solvent and the solution also includes an excipient toassist in elution of the therapeutic substance, wherein the excipientand therapeutic substance remain within the hollow stent afterextraction of residual solvent therefrom.
 12. The method of claim 11,wherein the excipient is a hydrophilic agent.
 13. The method of claim12, wherein the high capacity solvent is tetrahydrofuran, thetherapeutic substance is sirolimus and the excipient is urea.
 14. Themethod of claim 11, wherein the excipient is a surfactant.
 15. Themethod of claim 14, wherein the high capacity solvent is DCM, thetherapeutic substance is sirolimus and the excipient is a cyclodextrin.16. The method of claim 1, wherein the therapeutic substance is insolution and a solvent of the solution is a low-capacity solvent and thesolution also includes an excipient to assist in elution of thetherapeutic substance, wherein the excipient and therapeutic substanceremain within the hollow stent after extraction of residual solventtherefrom.
 17. The method of claim 16, wherein the excipient is asurfactant.
 18. The method of claim 17, wherein the low capacity solventis methanol, the therapeutic substance is sirolimus and the excipient isa cyclodextrin.
 19. The method of claim 16, wherein the excipient is ahydrophilic agent.
 20. The method of claim 19, wherein the low capacitysolvent is methanol, the therapeutic substance is sirolimus and theexcipient is urea.